Heteroaryl compounds as P2Y1 receptor inhibitors

ABSTRACT

The present invention provides novel heteroaryl compounds and analogues thereof, which are selective inhibitors of the human P2Y 1  receptor. The invention also provides for various pharmaceutical compositions of the same and methods for treating diseases responsive to modulation of P2Y 1  receptor activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the priority benefit of U.S. ProvisionalApplication No. 60/645,285, filed Jan. 19, 2005 and the priority benefitof U.S. Provisional Application No. 60/749,317, filed Dec. 9, 2005, allof which are expressly incorporated fully herein by reference.

FIELD OF THE INVENTION

The present invention provides novel heteroaryl compounds and analoguesthereof, which are selective inhibitors of the human P2Y₁ receptor. Theinvention also provides for various pharmaceutical compositions of thesame and methods for treating diseases responsive to modulation of P2Y₁receptor activity.

BACKGROUND OF THE INVENTION

Purinoreceptors bind to and are activated by a variety of bothribosylated (nucleotide) and non-ribosylated (nucleoside) purines. Thisdistinction has been used to classify these receptors into two broadgroups: the P1 receptors (A1, A2a, A2b and A3), which bind to and areactivated by the nucleoside adenosine, and the P2 receptors, whichcomprise a second, more diverse class of receptors which are activatedby a wide variety of nucleotides including ATP, ADP, UTP and UDP. The P2receptors can be further subdivided into two distinct types ofreceptors; the ionotropic P2X receptors that mediate cation flux acrosscellular membranes in response to ATP and the metabotropic P2Y family ofreceptors which are G-protein coupled receptors. In humans, the P2Yfamily of receptors is generally considered to consist of sevendistantly related members; P2Y₁, P2Y₂, P2Y₄, P2Y₆, P2Y₁₁, P2Y₁₂, andP2Y₁₃ (Boeynaems, J. M. et al. Drug Development Research 2000, 52,187-9). In addition, an eighth receptor, P2Y₁₄, has been considered bysome to be a member of this class although it does not respond toribosylated nucleotides and is activated by UDP-glucose (Abbracchio, M.P. et al. Trends Pharmacol. Sci. 2003, 24, 52-5).

Several studies have suggested that modulators of specific members ofthe P2Y family of receptors could have therapeutic potential for thetreatment of a variety of disorders (for review see Burnstock, G. andWilliams, M. J. Pharm. Exp Ther. 2000, 295, 862-9), including diabetes,cancer, CF, and treatment of ischemia-reperfusion injury (Abbracchio M.P., Burnstock G. Pharmacol. Ther. 1994, 64, 445-475). P2Y1 receptors,almost ubiquitous among human organs (Jassens R; Communi D.; Pirotton S.et al. Biochem. Biophys. Res. Comm. 1996, 221, 588-593) have beenidentified on microglia ( Norenberg W. et al.; Br. J. Pharmacol. 1994,111, 942-950) and on astrocytes (Salter M. W. and Hicks J. L. J.Neurosc. 1995, 15, 2961-2971). Extracellular ATP activates microglialand/or astrocytes via P2Y receptors and leads directly to the release ofinflammatory mediators. Microglia and astrocytes are believed to play arole in the progression of Alzheimer's disease and other CNSinflammatory disorders such as stroke and multiple sclerosis.

Two members of the P2Y family, P2Y₁ and P2Y₁₂, are of particularinterest as they have now both been shown to act as important receptorsfor ADP in platelets (Jin, J. et al. Proc. Natl. Acad. Sci. 1998, 95,8070). ADP is a key activator of platelets and platelet activation isknown to play a pivotal role in thrombus formation under conditions ofhigh shear stress such as those found in the arterial circulation. Inadditon, more recent data has suggested that platelet activation mayalso play a role in mediating thrombus formation under lower shearstress such as that found in the venous circulation. ADP activatesplatelets by simultaneously interacting with both P2Y₁ and P2Y₁₂ toproduce two separate intracellular signals which synergize together toproduce complete platelet activation (Jin, J. et al. Proc. Natl. Acad.Sci. 1998, 273, 2030-4). The first signal arises from ADP drivenactivation of the P2Y₁ receptor and can most easily be tracked bymeasuring the transitory increase in intracellular free Ca⁺². Thissignal appears to mediate the initial shape change reaction and toinitiate the process of platelet activation. The second signal appearsto be derived from ADP activation of the P2Y₁₂ receptor and serves toconsolidate the process and produce an irreversible platelet aggregate.Using three structurally related but distinct inhibitors of P2Y₁ (A3P5P,A3P5PS and A2P5P) (Daniel, J. L. et al. J. Biol. Chem. 1998, 273,2024-9; Savi, P. et al. FEBS Letters 1998, 422, 291-5; Hechler, B. etal. Br. J. Haematol. 1998, 103, 858-66.) were the first to publish theobservation that the inhibition of P2Y₁ activity alone could blockADP-driven aggregation independently of the P2Y₁₂ receptor. Althoughinhibition of platelet reactivity is often thought of as firm evidenceof an anti-thrombotic activity, these antagonists lacked the necessarypharmacological properties for in vivo study. The first directdemonstration that inhibition of P2Y₁ activity could lead to ananti-thrombotic effect in vivo was reported by Leon, C. et al.Circulation 2001, 103, 718-23, in a model of thromboplastin inducedthromboembolism using both a P2Y₁ knock-out mouse and the P2Y₁antagonist MRS-2179 (Baurand, A. and Gachet, C. Cardiovascular DrugReviews 2003, 21, 67-76). These results were subsequently extended toinclude the inhibition of both venous and arterial thrombosis in the rat(Lenain, N. er al. J. Thromb. Haemost. 2003, 1, 1144-9) and confirmed bya second laboratory using an independently derived P2Y₁ knock-out mouse(Fabre, J-E. et al. Nature Medicine 1999, 5, 1199-1202). Taken together,these data suggest that the discovery of novel P2Y₁ antagonists withimproved pharmaceutical characteristics could have significant utilityin the treatment of a variety of thromboembolic disorders.

SUMMARY OF THE INVENTION

The present invention provides novel heteroaryl compounds which areuseful as selective inhibitors of the P2Y₁ receptor includingstereoisomers, tautomers, pharmaceutically acceptable salts, solvates,or prodrugs thereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or a stereoisomer,tautomer, pharmaceutically acceptable salt, solvate, or prodrug formthereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a stereoisomer, tautomer, pharmaceutically acceptable salt,solvate, or prodrug form thereof.

The present invention also provides a method for modulation of plateletreactivity comprising administering to a host in need of such treatmenta therapeutically effective amount of at least one of the compounds ofthe present invention or a stereoisomer, tautomer, pharmaceuticallyacceptable salt, solvate, or prodrug form thereof.

The present invention also provides a method for treating thromboembolicdisorders comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, tautomer, pharmaceuticallyacceptable salt, solvate, or prodrug form thereof.

The present invention also provides novel thiazole and oxazolederivatives for use in therapy for other disease states which areresponsive to modulation of P2Y₁ activity.

The present invention also provides the use of novel thiazole andoxazole derivatives for the manufacture of a medicament for thetreatment of a thromboembolic or other disorders.

These and other features of the invention will be set forth in theexpanded form as the disclosure continues.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In a first embodiment, the present invention provides, inter alia,compounds of Formula (Ia):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein:

-   -   ring A is a 5- to 6-membered heteroaryl comprising: carbon atoms        and 1-4 ring heteroatoms selected from N, NR¹¹, S(O)_(p), and O,        wherein said heteroaryl is substituted with 0-4 R¹;    -   ring B is phenyl substituted with 0-4 R⁷, pyridyl substituted        with 0-3 R⁷, or thienyl substituted with 0-2 R⁷;    -   X is NH or NMe;    -   Y is O or S;    -   R¹ is, independently at each occurrence, F, Cl, Br, I, CF₃,        —CF₂CF₃, OCF₃, —OCF₂CF₂H, —OCF₂CF₃, SiMe₃,        —(CR^(f)R^(f))_(r)—OR^(c), SR^(c), CN, NO₂,        —(CR^(f)R^(f))_(r)—NR¹²R¹³, —(CR^(f)R^(f))_(r)—C(O)R^(c),        —(CR^(f)R^(f))_(r)—CO₂R^(c), —(CR^(f)R^(f))_(r)—C(O)NR¹²R¹³,        —C(O)NR¹⁴(CR^(f)R^(f))_(t)N¹²R¹³,        —(CR^(f)R^(f))_(r)—OC(O)NR¹²R¹³,        —(CR^(f)R^(f))_(r)—NR¹⁴C(O)NR¹²R¹³,        —(CR^(f)R^(f))_(r)—NR¹⁴C(O)R^(d),        —(CR^(f)R^(f))_(r)—NR¹⁴C(O)OR^(h),        —NR¹⁴(CR^(f)R^(f))_(n)C(O)R^(d), —NR¹⁴CO(CR^(f)R^(f))_(n)OR^(c),        —(CH₂)_(r)—CR¹³(═NOR^(c)), —(CH₂)_(r)—C(NH₂)(═NOR^(c)),        —S(O)_(p)NR¹²R¹³, —(CR^(f)R^(f))_(r)—NR¹⁴S(O)_(p)NR¹²R¹³,        —NR¹⁴SO₂CF₃, —NR¹⁴S(O)_(p)R^(d), —S(O)₂CF₃, —S(O)R^(d),        —S(O)₂R^(d), —OP(O)(OEt)₂, —O(CH₂)₂OP(O)(OEt)₂,        4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl, C₁₋₈ alkyl substituted        with 0-2 R^(a), C₂₋₈ alkenyl substituted with 0-2 R^(a), C₂₋₈        alkynyl substituted with 0-2 R^(a), —(CR^(f)R^(f))_(r)—C₃₋₁₃        carbocycle substituted with 0-5 R^(b), or —(CR^(f)R^(f))_(r)-5-        to 10-membered heterocycle comprising: carbon atoms and 1-4        heteroatoms selected from N, NR¹¹, O, and S(O)_(p), wherein said        heterocycle is substituted with 0-5 R^(b);    -   alternatively, two R¹s are combined with the carbon atoms to        which they attached, form a 5- to 7-membered carbocycle or        heterocycle comprising: carbon atoms and 0-3 additional        heteroatoms selected from N, NR¹¹, O, and S(O)_(p), 0-2        carbonyls, and 0-2 double bond, wherein said carbocycle or        heterocycle is substituted with 0-4 R^(b);    -   R⁵ is a —(CR^(f)R^(f))_(n)—C₃₋₁₀ carbocycle substituted with 1-4        R^(5a), or a —(CR^(f)R^(f))_(n)-5- to 10-membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from N,        NR¹¹, O, and S(O)_(p), wherein said heterocycle is substituted        with 0-4 R^(5a);    -   R^(5a) is, independently at each occurrence, F, Cl, Br, I,        —(CR^(i)R^(i))_(r)—OR^(c), SR^(c), CN, NO₂, CF₃, —CF₂CF₃, OCF₃,        —OCF₂CF₂H, —OCF₂CF₃, —NR¹²R¹³, —C(O)R^(c), —C(O)OR^(c),        —C(O)NR¹²R¹³, —NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³, —S(O)R^(d),        —S(O)₂R^(d), —Si(Me)₃, Si(C₁₋₄ alkyl)₃, C₁₋₄ haloalkyl, C₁₋₄        haloalkyloxy-, C₁₋₄ alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄        alkyl-C(O)—, C₁₋₄ alkyl-O—C(O)—, C₁₋₄ alkyl-C(O)NH—, C₁₋₈ alkyl        substituted with 0-2 R^(a), C₂₋₈ alkenyl substituted with 0-2        R^(a), C₂₋₈ alkynyl substituted with 0-2 R^(a),        —(CR^(f)R^(f))_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(e),        or —(CR^(f)R^(f))_(r)-5- to 10-membered heterocycle comprising:        carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and        S(O)_(p), wherein said heterocycle is substituted with 0-3        R^(e);    -   alternatively, two R^(5a) groups, together with the atoms to        which they are attached, form a 5- to 7-membered carbocyclic or        heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms        selected from N, NR¹¹, O, and S(O)_(p), 0-1 carbonyl and 0-3        double bonds, wherein said carbocyclic or heterocyclic ring is        substituted with 0-3 R_(e);    -   R⁷ is, independently at each occurrence, H, F, Cl, Br, I, OCF₃,        CF₃, OR^(c), SR^(c), CN, NO₂, —NR¹²R¹³, —C(O)R^(c), —C(O)OR^(c),        —C(O)NR¹²R¹³, —NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³, —S(O)R^(d),        —S(O)₂R^(d), C₁₋₈ alkyl substituted with 0-2 R^(a), C₂₋₈ alkenyl        substituted with 0-2 R^(a), C₂₋₈ alkynyl substituted with 0-2        R^(a), —(CR^(f)R^(f))_(r)—C₃₋₁₀ carbocycle substituted with 0-3        R^(b), or —(CR^(f)R^(f))_(r)-5- to 10-membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from N,        NR^(7b), O, and S(O)_(p), wherein said heterocycle is        substituted with 0-3 R^(b);    -   alternatively, two R⁷s can form a 5- to 7-membered carbocyclic        or heterocyclic ring comprising: carbon atoms and 0-3 ring        heteroatoms selected from O, N, NR^(7b), and S(O)_(p), wherein        said carbocyclic or heterocyclic ring is substituted with 0-3        R^(7c);    -   R^(7b) is, independently at each occurrence, H, C₁₋₄ alkyl,        (C₁₋₄ alkyl)C(O)—, phenyl-C(O)—, benzyl-C(O)—, benzyl-S(O)₂—,        (C₁₋₄ alkyl)NHC(O)—, (C₁₋₄ alkyl)₂NC(O)—, phenyl-NHC(O)—,        benzyl-NHC(O)—, (C₁₋₄ alkyl)-S(O)₂—, phenyl-S(O)₂—, phenyl        substituted with 0-3 R^(b), or benzyl substituted with 0-3        R^(b);    -   R^(7c) is, independently at each occurrence, H, F, Cl, Br, I,        OCF₃, CF₃, OR^(c), SR^(c), CN, NO₂, —NR¹²R¹³, —C(O)R^(c),        —C(O)OR^(c), —C(O)NR¹²R¹³, —NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³,        —S(O)R^(d), —S(O)₂R^(d), C₁₋₄ alkyl, phenyl substituted with 0-3        R^(b), or benzyl substituted with 0-3 R^(b);    -   R¹¹ is, independently at each occurrence, H, C₁₋₆ alkyl        substituted with 1-5 fluorine, —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³,        C₁₋₈ alkyl substituted with 0-2 R^(a), C₂₋₈ alkenyl substituted        with 0-2 R^(a), C₂₋₈ alkynyl substituted with 0-2 R^(a), (C₁₋₆        alkyl)C(O)—, (C₃₋₆ cycloalkyl)C₁₋₃ alkyl-C(O)—, (C₃₋₆        cycloalkyl)C(O)—, phenyl-C(O)—, benzyl-C(O)—, (C₁₋₆        alkyl)NHC(O)—, (C₁₋₆ alkyl)₂NC(O)—, phenyl-NHC(O)—,        benzyl-NHC(O)—, (phenyl)(C₁₋₆ alkyl)NC(O)—, (benzyl)(C₁₋₆        alkyl)NC(O)—, (C₁₋₆ alkyl)-S(O)₂—, phenyl-S(O)₂—, benzyl-S(O)₂—,        —(CR^(f)R^(f))_(r)—C₃₋₁₀ carbocycle, or —(CR^(f)R^(f))_(r)-5- to        10-membered heterocycle comprising: carbon atoms and 1-4        heteroatoms selected from N, NR^(f), O, and S(O)_(p); wherein        said phenyl, benzyl, carbocycle, and heterocycle are substituted        with 0-3 R^(b);    -   R¹² is, independently at each occurrence, H, C₁₋₆ alkyl        substituted with 1-5 fluorine,        —(CR^(f)R^(f))_(r)C(O)NR^(f)R^(f), C₁₋₆ alkyl, (C₁₋₆        alkyl)C(O)—, (C₁₋₄ alkyl)OC(O)—, (C₆₋₁₀ aryl)-CH₂—OC(O)—, (C₆₋₁₀        aryl)-CH₂—C(O)—, (C₁₋₄ alkyl)-C(O)O—(C₁₋₄ alkyl)-OC(O)—, (C₆₋₁₀        aryl)-C(O)O—(C₁₋₄ alkyl)-OC(O)—, (C₁₋₆ alkyl)-NHC(O)—, (C₆₋₁₀        aryl)-NHC(O)—, (5- to 10-membered heteroaryl)-NHC(O)—, (5- to        10-membered heteroaryl)-CH₂—OC(O)—, (5- to 10-membered        heteroaryl)-C(O)—, (C₆₋₁₀ aryl)-(C₀₋₄ alkyl)-C(O)—, (C₁₋₆        alkyl)-S(O)₂—, (C₆₋₁₀ aryl)-S(O)₂—, (5- to 10-membered        heteroaryl)-S(O)₂—, or (C₆₋₁₀ aryl)-(C₁₋₄ alkyl)-S(O)₂—,        —(CR^(f)R^(f))_(n)—(C₆₋₁₀ aryl), —(CR^(f)R^(f))_(n)-5- to        10-membered heterocycle; wherein said alkyl, phenyl and aryl are        substituted with 0-2 R^(g); said 5- to 10-membered heteroaryl is        substituted with with 0-2 R^(g) and comprises: carbon atoms and        1-4 heteroatoms selected from N, NR^(f), O, and S(O)_(p); said        5- to 10-membered heterocycle is substituted with with 0-2 R^(g)        and comprises: carbon atoms and 1-4 heteroatoms selected from N,        NR^(f), O, and S(O)_(p);    -   R¹³ is, independently at each occurrence, H, C₁₋₆ alkyl, or        —(CH₂)_(n)-phenyl;    -   alternatively, R¹² and R¹³, when attached to the same nitrogen,        combine to form a 5- to 10-membered heterocyclic ring        comprising: carbon atoms and 1-2 additional heteroatoms selected        from N, NR^(f), O, and S(O)_(p);    -   R¹⁴ is, independently at each occurrence, H, C₁₋₆ alkyl        substituted with 0-2 R^(14a), C₂₋₆ alkenyl substituted with 0-2        R^(14a), C₂₋₆ alkynyl substituted with 0-2 R^(14a),        —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(g), or        —(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon        atoms and 1-4 heteroatoms selected from N, NR^(f), O, and        S(O)_(p), wherein said heterocycle is substituted with 0-3        R^(g);    -   R^(14a) is, independently at each occurrence, H, C₁₋₄ alkyl,        OR^(f), Cl, F, Br, I, ═O, CF₃, CN, NO₂, NR¹²R¹³, —C(O)R^(f),        —C(O)OR^(f), —C(O)NR¹²R¹³, or —S(O)_(p)R^(f);    -   R^(a) is, independently at each occurrence, H, F, OCF₃, CF₃,        —(CR^(f)R^(f))_(r)OR^(c), —(CR^(f)R^(f))_(r)SR^(c), CN,        —(CR^(f)R^(f))_(r)NR¹²R¹³, —(CR^(f)R^(f))_(r)C(O)R^(c),        —(CR^(f)R^(f))_(r)C(O)OR^(c), —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³,        —(CR^(f)R^(f))_(r)NR¹⁴C(O)R^(d),        —(CR^(f)R^(f))_(r)S(O)_(p)NR¹²R¹³, —(CR^(f)R^(f))_(r)S(O)R^(d),        —(CR^(f)R^(f))_(r)S(O)₂R^(d), C₁₋₄ alkyl substituted with 1-5        fluorine, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3        R^(e), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:        carbon atoms and 1-4 heteroatoms selected from N, NR^(f), O, and        S(O)_(p), wherein said heterocycle is substituted with 0-3        R^(e);    -   R^(b) is, independently at each occurrence, H, ═O, F, Cl, Br, I,        —(CH₂)_(r)—OR^(c), SR^(c), CN, NO₂, CF₃, OCF₃,        —(CR^(f)R^(f))_(r)NR¹²R¹³, —C(O)R^(c), —(CH₂)_(r)—C(O)OR^(c),        —(CH₂)_(r)—C(O)NR¹²R¹³, —NR¹⁴C(O)R^(d),        —S(O)_(p)NR¹²R¹³,—S(O)R^(d), —S(O)₂R^(d), C₁₋₄ haloalkyl, C₁₋₄        haloalkyloxy-, C₁₋₆ alkyl substituted with 0-2 R^(a), C₂₋₆        alkenyl substituted with 0-2 R^(a), C₂₋₆ alkynyl substituted        with 0-2 R^(a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3        R^(e), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:        carbon atoms and 1-4 heteroatoms selected from N, NR^(f), O, and        S(O)_(p), wherein said heterocycle is substituted with 0-3        R^(e);    -   R^(c) is, independently at each occurrence, H, —OP(O)(OEt)₂,        C₁₋₈ alkyl substituted with 0-2 R^(e), C₂₋₈ alkenyl substituted        with 0-2 R^(e), C₂₋₈ alkynyl substituted with 0-2 R^(e),        —(CR^(f)R^(f))_(r)—C₃₋₈ cycloalkyl substituted with 0-2 R^(e),        —(CR^(f)R^(f))_(r)—C₆₋₁₀ aryl substituted with 0-2 R^(e), or        —(CR^(f)R^(f))_(r)-5- to 10-membered heterocycle comprising:        carbon atoms and 1-4 heteroatoms selected from N, NR^(f), O, and        S(O)_(p), wherein said heterocycle is substituted with 0-2        R^(e);    -   R^(d) is, independently at each occurrence, CF₃, OH, C₁₋₄        alkoxy, C₁₋₆ alkyl, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with        0-2 R^(e), or —(CH₂)_(r)-5- to 10-membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from N,        NR^(f), O, and S(O)_(p), wherein said heterocycle is substituted        with 0-2 R^(e);    -   R^(e) is, independently at each occurrence, H, ═O,        —(CH₂)_(r)—OR^(f), F, Cl, Br, I, CN, NO₂, —(CH₂)_(r)—NR¹²R¹³,        —C(O)R^(f), —(CH₂)_(r)—C(O)OR^(f), —NR¹⁴C(O)R^(f),        —(CH₂)_(r)—C(O)NR¹²R¹³, —SO₂NR¹²R¹³, —NR¹⁴SO₂NR¹²R¹³,        —NR¹⁴SO₂—C₁₋₄ alkyl, —NR¹⁴SO₂CF₃, —NR¹⁴SO₂-phenyl, —S(O)₂CF₃,        —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, —(CF₂)_(r)CF₃, Si(C₁₋₄        alkyl)₃, C₁₋₈ alkyl substituted with 0-2 R^(g), C₂₋₈ alkenyl        substituted with 0-2 R^(g), C₂₋₈ alkynyl substituted with 0-2        R^(g), —(CH₂)_(r)—C₃₋₈ cycloalkyl substituted with 0-2 R^(g),        —(CH₂)_(r)—C₆₋₁₀ aryl substituted with 0-2 R^(g), or        —(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon        atoms and 1-4 heteroatoms selected from N, NR^(f), O, and        S(O)_(p), wherein said heterocycle is substituted with 0-2        R^(g);    -   alternatively, two R^(e) groups, together with the atoms to        which they are attached, form a 5- to 7-membered carbocyclic or        heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms        selected from N, NR^(f), O, and S(O)_(p), 0-1 carbonyl and 0-3        double bonds, wherein said carbocyclic or heterocyclic ring is        substituted with 0-3 R^(g);    -   R^(f) is, independently at each occurrence, H, F, C₁₋₆ alkyl, or        —(CH₂)_(n)-phenyl;    -   R^(g) is, independently at each occurrence, H, ═O, OR^(f), F,        Cl, Br, I, CN, NO₂, —NR^(f)R^(f), —C(O)R^(f), —C(O)OR^(f),        —NR^(f)C(O)R^(f), —C(O)NR^(f)R^(f), —SO₂NR^(f)R^(f),        —NR^(f)SO₂NR^(f)R^(f), —NR^(f)SO₂—C₁₋₄ alkyl, —NR^(f)SO₂CF₃,        —NR^(f)SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl,        —S(O)_(p)-phenyl, —(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, or        C₂₋₆ alkynyl;    -   R^(h) is, independently at each occurrence, C₁₋₆ alkyl        substituted with 0-2 R^(g), or —(CH₂)_(n)-phenyl substituted        with 0-2 R^(g), or —(CH₂)_(n)-5- to 10-membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from N,        NR^(f), O, and S(O)_(p), wherein said heterocycle is substituted        with 0-2 R^(g);    -   R^(i) is, independently at each occurrence, H, C₁₋₆ alkyl        substituted with 0-2 R^(g), —(CH₂)_(n)-phenyl substituted with        0-2 R^(g), or —(CH₂)_(n)-5- to 10-membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from N,        NR^(f), O, and S(O)_(p), wherein said heterocycle is substituted        with 0-2 R^(g);    -   n, at each occurrence, is selected from 0, 1, 2, 3, and 4;    -   p, at each occurrence, is selected from 0, 1, and 2; and    -   r, at each occurrence, is selected from 0, 1, 2, 3, and 4;    -   provided that:        -   i) when R⁵ is pyridyl substituted with NO₂, then ring A is            other than pyridyl substituted with NO₂;        -   ii) when Y is S, ring B is phenylene or phenylene            substituted with Cl, R⁵ is phenyl substituted with Cl, then            ring A is other than pyridyl substituted with CO₂H;        -   iii) when Y is S, ring B is phenylene, R⁵ is phenyl            substituted with —NH-pyridyl, then ring A is other than            pyridyl;        -   iv) when Y is O, ring B is phenylene substituted with Cl, R⁵            is pyridyl, then ring A is other than trizolyl substituted            with CO₂H; or        -   v) when Y is O, ring B is phenylene, R⁵ is phenyl            substituted with —NH-thiazolyl or —NH-(4-Me-thiazolyl), then            ring A is other than thiazolyl or 4-Me-thiazolyl.

In a second embodiment, the present invention includes compounds ofFormula (Ia), or a stereoisomer, tautomer, pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein: ring B is pyridylsubstituted with 0-3 R⁷.

In another embodiment, the present invention includes compounds ofFormula (Ia), or a stereoisomer, tautomer, pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein: ring B is substituted with0-3 R⁷ and selected from:

In another embodiment, the present invention includes compounds ofFormula (Ia), or a stereoisomer, tautomer, pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein: ring B is

In a third embodiment, the present invention includes compounds ofFormula (Ia), or a stereoisomer, tautomer, pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein: ring A is substituted with0-3 R¹ and selected from:

In another embodiment, the present invention includes compounds ofFormula (Ia), or a stereoisomer, tautomer, pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein: ring A is substituted with0-3 R¹ and selected from:

In a fourth embodiment, the present invention includes the compounds ofFormula (Ia), or a stereoisomer, tautomer, pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein:

-   -   ring B is    -   R⁷ and R^(7a) are H, Me, Cl, Br, CN, OMe, SMe, NHMe, NH₂, NMe₂,        or —NH(4-OMe-Ph);    -   R⁸ and R^(8b) are H, Me, Cl, Br, CN, NMe₂, or —N(Me)(4-OMe-Ph);    -   X is NH; and    -   Y is O, S, or NH.

In a fifth embodiment, the present invention includes compounds ofFormula (II):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvates,or prodrug thereof, wherein:

-   -   ring A is selected from:    -   alternatively, ring A is substituted with 0-3 R¹ and is selected        from:    -   R¹, R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) are,        independently at each occurrence, C₁₋₆ alkyl substituted with        0-2 R^(a), C₂₋₆ alkenyl substituted with 0-2 R^(a), C₂₋₆ alkynyl        substituted with 0-2 R^(a), Br, CN, CF₃, —CF₂CF₃, —C(NH₂)═N(OH),        C(O)R^(c), —CH(═NOH), —C(O)OR^(c), NR¹²R¹³, —C(O)NR¹²R¹³,        —CON(Me)(CH₂)₂OH, —CO-morpholin-4-yl, —SO₂-morpholin-4-yl,        —S(O)_(p)NR¹²R¹³, —(CH₂)_(r)—C₃₋₆ cycloalkyl substituted with        0-2 R^(b), —(CH₂)_(r)-adamantyl substituted with 0-2 R^(b),        —(CH₂)_(r)-phenyl substituted with 0-4 R^(b),        —(CH₂)_(r)-naphthyl substituted with 0-4 R^(b), —(CH₂)_(r)-3- to        10-membered heterocycle substituted with 0-4 R^(b), wherein said        heterocycle is selected from: aziridinyl, azetidinyl,        pyrrolidinyl, fliranyl, imidazolyl, oxadiazolyl, thienyl,        pyrrolyl, isoxazolyl, triazolyl, tetrazolyl, pyridinyl,        pyrazinyl, pyrimidinyl, piperdinyl, morpholinyl, piperazinyl,        1,3-benzodioxolyl, benzothienyl, isoindolinyl,        1,4-diazacycloheptanyl, tetrahydroisoquinolyl, and    -   alternatively, R^(1a) and R^(1b) or R^(1d) and R^(1e) are        combined with the carbon atoms to which they attached, form a 5-        to 6-membered carbocycle or heterocycle comprising: carbon atoms        and 0-3 additional heteroatoms selected from N, NR¹¹, O, and        S(O)_(p), 0-2 carbonyl, and 0-1 additional double bond, wherein        said carbocycle and heterocycle are substituted with 0-3 R^(b);    -   alternatively, two R¹s are combined with the carbon atoms to        which they attached, form a 5- to 6-membered carbocycle or        heterocycle comprising: carbon atoms and 0-3 additional        heteroatoms selected from N, NR¹¹, O, and S(O)_(p), 0-2        carbonyl, and 0-1 additional double bond, wherein said        carbocycle and heterocycle are substituted with 0-3 R^(b);    -   R⁵ is phenyl substituted with 1-4 R^(5a);    -   R^(5a) is, independently at each occurrence, F, Cl, Br, I,        —(CR^(i)R^(i))_(r)—OR^(c), SR^(c), CN, CF₃, —CF₂CF₃, OCF₃,        —OCF₂CF₂H, —OCF₂CF₃, —NR¹²R¹³, —C(O)R^(c), —C(O)OR^(c),        —C(O)NR¹²R¹³, —NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³, —S(O)R^(d),        —S(O)₂R^(d), —Si(Me)₃, Si(C₁₋₄ alkyl)₃, C₁₋₄ haloalkyl, C₁₋₄        haloalkyloxy-, C₁₋₄ alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄        alkyl-C(O)—, C₁₋₄ alkyl-O—C(O)—, C₁₋₄ alkyl-C(O)NH—, C₁₋₈ alkyl        substituted with 0-2 R^(a), C₂₋₈ alkenyl substituted with 0-2        R^(a), C₂₋₈ alkynyl substituted with 0-2 R^(a),        —(CR^(f)R^(f))_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(e),        or —(CR^(f)R^(f))_(r)-5- to 10-membered heterocycle comprising:        carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and        S(O)_(p), wherein said heterocycle is substituted with 0-3        R^(e);    -   alternatively, two R^(5a) groups attached to two adjacent carbon        atoms, together with the carbon atoms to which they are        attached, form a 5- to 7-membered carbocyclic or heterocyclic        ring comprising: carbon atoms and 0-2 heteroatoms selected from        N, NR¹¹, O, and S(O)_(p), 0-1 carbonyl and 0-3 double bonds,        wherein said carbocyclic or heterocyclic ring is substituted        with 0-3 R^(e);    -   R⁷ is H, Br, CN, NH₂, NMe₂, or —NH(4-OMe-Ph);    -   R⁸ is H, Br, CN, NMe₂, or —N(Me)(4-OMe-Ph);    -   R¹¹ is, independently at each occurrence, H, —COPh, —COBn,        —SO₂Me, —SO₂Ph, —SO₂Bn, C₁₋₆ alkyl substituted with 1-5        fluorine, —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³, C₁₋₄ alkyl substituted        with 0-2 R^(a), —(CH₂)_(r)—C₃₋₆ cycloalkyl substituted with 0-2        R^(b), —(CH₂)_(r)-phenyl substituted with 0-3 R^(b),        —CHMe-phenyl substituted with 0-3 R^(b), or —(CH²)_(r)-5- to        10-membered heterocycle substituted with 0-3 R^(b); wherein said        heterocycle is selected from: furanyl, thienyl, thiazolyl,        pyridyl, and indolyl;    -   R¹² is, independently at each occurrence, H, C₁₋₆ alkyl        substituted with 1-5 fluorine,        —(CR^(f)R^(f))_(r)C(O)NR^(f)R^(f), C₁₋₆ alkyl, —(CH₂)_(r)—C₃₋₆        cycloalkyl, —(CH₂)_(n)-phenyl, —(CH₂)_(r)-5- to 6-membered        heterocycle selected from pyrrolidinyl, furanyl, thienyl,        pyrrolyl, isoxazolyl, triazolyl, tetrazolyl, pyridinyl,        pyrazinyl, pyrimidinyl, piperdinyl, morpholinyl, and        piperazinyl; wherein said alkyl and phenyl are substituted with        0-2 R^(g); said 5- to 10-membered heterocycle is substituted        with with 0-2 R^(g);    -   R¹³ is, independently at each occurrence, H, C₁₋₆ alkyl, or        —(CH₂)_(n)-phenyl;    -   alternatively, R¹² and R¹³, when attached to the same nitrogen,        combine to form a 5- to 10-membered heterocyclic ring        comprising: carbon atoms and 1-2 additional heteroatoms selected        from N, NR^(f), O, and S(O)_(p);    -   R¹⁴ is, independently at each occurrence, H, C₁₋₆ alkyl, C₂₋₆        alkenyl, —(CH₂)_(r)-phenyl carbocycle substituted with 0-3        R^(g), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:        carbon atoms and 1-4 heteroatoms selected from N, NR^(f), O, and        S(O)_(p), wherein said heterocycle is substituted with 0-3        R^(g);    -   R^(a) is, independently at each occurrence, H, F, OCF₃, CF₃,        —(CR^(f)R^(f))_(r)OR^(c), —(CR^(f)R^(f))_(r)SR^(c), CN,        —(CR^(f)R^(f))_(r)NR¹²R¹³, —(CR^(f)R^(f))_(r)C(O)R^(c),        —(CR^(f)R^(f))_(r)C(O)OR^(c), —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³,        —(CR^(f)R^(f))_(r)NR¹⁴C(O)R^(d),        —(CR^(f)R^(f))_(r)S(O)_(p)NR¹²R¹³, —(CR^(f)R^(f))_(r)S(O)R^(d),        —(CR^(f)R^(f))_(r)S(O)₂R^(d), C₁₋₄ alkyl substituted with 1-5        fluorine, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3        R^(e), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:        carbon atoms and 1-4 heteroatoms selected from N, NR^(f), O, and        S(O)_(p), wherein said heterocycle is substituted with 0-3        R^(e);    -   R^(b) is, independently at each occurrence, C₁₋₆ alkyl        substituted with 0-2 R^(a), C₂₋₆ alkenyl substituted with 0-2        R^(a), C₂₋₆ alkynyl substituted with 0-2 R^(a), F, Cl, Br, CF₃,        —OCF₃, —(CH₂)_(r)—OR^(c), —(CH₂)_(r)—C(O)OR^(c),        —(CR^(f)R^(f))_(r)NR¹²R¹³, —(CH₂)_(r)—C(O)NR¹²R¹³, CN,        —OCH₂C(Me)₂CH₂NMe₂, NO₂, —SO₂Me, OBn, —(CH₂)_(r)—C₃₋₆        cycloalkyl, —(CH₂)_(r)-phenyl substituted with 0-2 R^(e),        —(CH₂)_(r)-naphthyl substituted with 0-3 R^(e), —(CH₂)_(r)-5- to        10-membered heterocycle substituted with 0-4 0-4 R^(e); wherein        said heterocycle is selected from: thienyl, thiazolyl,        imidazolyl, tetrazolyl, pyrrolidinyl, morpholinyl, piperidinyl,        azepanyl, morpholinyl, piperazinyl, pyridinyl,        tetrahydropyranyl, or tetrahydroisoquinolinyl;    -   R^(d) is, independently at each occurrence, CF₃, OH, C₁₋₄        alkoxy, C₁₋₆ alkyl, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with        0-2 R^(e), or —(CH₂)_(r)-5- to 10-membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from N,        NR^(f), O, and S(O)_(p), wherein said heterocycle is substituted        with 0-2 R^(e);    -   R^(e) is, independently at each occurrence, H, ═O,        —(CH₂)_(r)—OR^(f), F, Cl, Br, I, CN, NO₂, —(CH₂)_(r)—NR¹²R¹³,        —C(O)R^(f), —(CH₂)_(r)—C(O)OR^(f), —NR¹⁴C(O)R^(f),        —(CH₂)_(r)—C(O)NR¹²R¹³, —SO₂NR¹²R¹³, —NR¹⁴SO₂NR¹²R¹³,        —NR¹⁴SO₂—C₁₋₄ alkyl, —NR¹⁴SO₂CF₃, —NR¹⁴SO₂-phenyl, —S(O)₂CF₃,        —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, —(CF₂)_(r)CF₃, Si(C₁₋₄        alkyl)₃, C₁₋₈ alkyl substituted with 0-2 R^(g), C₂₋₈ alkenyl        substituted with 0-2 R^(g), C₂₋₈ alkynyl substituted with 0-2        R_(g), —(CH₂)_(r)—C₃₋₈ cycloalkyl substituted with 0-2 R^(g),        —(CH₂)_(r)—C₆₋₁₀ aryl substituted with 0-2 R^(g), or        —(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon        atoms and 1-4 heteroatoms selected from N, NR^(f), O, and        S(O)_(p), wherein said heterocycle is substituted with 0-2        R^(g);    -   alternatively, two R^(e) groups, together with the atoms to        which they are attached, form a 5- to 7-membered carbocyclic or        heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms        selected from N, NR^(f), O, and S(O)_(p), 0-1 carbonyl and 0-3        double bonds, wherein said carbocyclic or heterocyclic ring is        substituted with 0-2 R^(g);    -   R^(f) is, independently at each occurrence, H, F, C₁₋₆ alkyl, or        —(CH₂)_(n)-phenyl;    -   R^(g) is, independently at each occurrence, H, ═O, OR^(f), F,        Cl, Br, I, CN, NO₂, —NR^(f)R^(f), —C(O)R^(f), —C(O)OR^(f),        —NR^(f)C(O)R^(f), —C(O)NR^(f)R^(f), —SO₂NR^(f)R^(f),        —NR^(f)SO₂NR^(f)R^(f), —NR^(f)SO₂—C₁₋₄ alkyl, —NR^(f)SO₂CF₃,        —NR^(f)SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl,        —S(O)_(p)-phenyl, —(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, or        C₂₋₆ alkynyl;    -   R^(i) is, independently at each occurrence, H or C₁₋₆ alkyl;    -   n, at each occurrence, is selected from 0, 1, 2, 3, and 4;    -   p, at each occurrence, is selected from 0, 1, and 2; and    -   r, at each occurrence, is selected from 0, 1, 2, 3, and 4.

In a sixth embodiment, the present invention includes compounds ofFormula (II), or a stereoisomer, tautomer, pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein:

-   -   ring A is    -   R^(1a) and R^(1b), independently at each occurrence, H, C₁₋₆        alkyl substituted with 0-2 R^(a), C₂₋₆ alkenyl substituted with        0-2 R^(a), C₂₋₆ alkynyl substituted with 0-2 R^(a), Br, CN, CF₃,        —CF₂CF₃, —C(NH₂)═N(OH), C(O)R^(c), —C(O)OR^(c), NR¹²R¹³,        —C(O)NR¹²R¹³, —CON(Me)(CH₂)₂OH, —SO₂-morpholin-4-yl,        —S(O)_(p)NR¹²R¹³, —CO-(4-morpholinyl), —(CH₂)_(r)-phenyl        substituted with 0-3 R^(b); —(CH₂)_(r)-3- to 10-membered        heterocycle substituted with 0-3 R^(b); wherein said heterocycle        is selected from: aziridinyl, pyrrolidinyl, furanyl, imidazolyl,        oxadiazolyl, triazolyl, tetrazolyl, piperidinyl, morpholinyl,        piperazinyl, pyridyl, pyrimidinyl, 1,3-benzodioxolyl,        isoindolinyl, 1,4-diazacycloheptanyl, tetrahydroisoquinolinyl,        or    -   alternatively, ring A is    -   R¹¹ is H, C₁₋₆ alkyl substituted with 1-5 fluorine,        —CH₂CH₂O(C₁₋₄ alkyl), —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³, C₁₋₆ alkyl,        cyclopropylmethyl, cyclopentylmethyl, —(CH₂)₂OH, Bn, —COPh,        —COBn, —SO₂Me, —SO₂Ph, —SO₂Bn, —(CH₂)_(r)-phenyl substituted        with 0-2 R^(b), or —(CH₂)_(r)-5- to 6-membered heterocycle        substituted with 0-2 R^(b), wherein said heterocycle is selected        from: furanyl, thienyl, thiazolyl, and pyridyl;    -   R^(a) is, independently at each occurrence, OH, OMe,        —C(O)OR^(c), —(CR^(f)R^(f))_(r)NR¹²R¹³,        —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³, C₁₋₄ alkyl substituted with 1-5        fluorine, or —CO(4-morpholinyl);    -   R^(b) is, independently at each occurrence, C₁₋₆ alkyl, F, CF₃,        —OCF₃, OH, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, OMe, —CH₂OMe,        —OCH₂C(Me)₂CH₂NMe₂, CO₂H, —CH₂CH₂CO₂H, CO₂Me, —CH₂CH₂CO₂Me,        CO₂Et, CN, —CH₂NHMe, —CH₂NHEt, —CH₂NHBn, NMe₂, —CH₂NMe₂,        —CH₂N(Me)Et, —CH₂N(Me)Bn, —CH₂CH₂CH₂N(Me)Et, NO₂, —SO₂Me, OBn,        cyclopropylmethyl, tetrahydropyranyl, pyrrolidinyl,        pyrrolidinylmethyl, or morpholinylethyl.

In a seventh embodiment, the present invention includes compounds ofFormula (II), or a stereoisomer, tautomer, pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein:

-   -   ring A is selected from:    -   R^(1c) is, independently at each occurrence, C₁₋₆ alkyl        substituted with 0-2 R^(a), C₂₋₆ alkenyl substituted with 0-2        R^(a), C₂₋₆ alkynyl substituted with 0-2 R^(a), Br, CF₃,        C(O)R^(c), —C(O)OR^(c), NR¹²R¹³, —C(O)NR¹²R¹³, —(CH₂)_(r)—C₃₋₆        cycloalkyl substituted with 0-2 R^(b), —(CH₂)_(r)-adamantyl        substituted with 0-2 R^(b), —(CH₂)_(r)-phenyl substituted with        0-3 R^(b), —(CH₂)_(r)-naphthyl substituted with 0-3 R^(b),        —C(Me)₂(CH₂)_(r)-piperazinyl substituted with 0-3 R^(b),        —C(Me)₂(CH₂)_(r)CO-piperazinyl substituted with 0-3 R^(b),        —(CH₂)_(r)-5- to 10-membered heterocycle substituted with 0-3        R^(b); wherein said heterocycle is selected from: azetidinyl,        pyrrolidinyl, furanyl, thienyl, pyrrolyl, isoxazolyl, triazolyl,        pyridinyl, pyrazinyl, piperdinyl, piperazinyl, benzothienyl,        isoindolinyl, and tetrahydroisoquinolinyl;    -   R^(a) is, independently at each occurrence, —O(CH₂)₂OMe,        —C(O)OR^(c), —(CR^(f)R^(f))_(r)NR¹²R¹³,        —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³, C₁₋₄ alkyl substituted with 1-5        fluorine, SPh, phenoxy substituted with 0-2 R^(e), or benzoxy        substituted with 0-2 R^(e);    -   R^(b) is, independently at each occurrence, C₁₋₆ alkyl, C₁₋₄        alkoxyl, F, Cl, CF₃, —OCF₃, OH, —CH₂OH, CN,        —(CR^(f)R^(f))_(r)NR¹²R¹³, —CH₂NMe₂, NO₂, —SO₂Me,        —(CH₂)_(r)—C₃₋₆ cycloalkyl, CH(Ph)₂, —(CH₂)_(r)-phenyl        substituted with 0-2 R^(e), —(CH₂)_(r)-naphthyl substituted with        0-3 R^(e), —(CH₂)_(r)-furyl substituted with 0-2 R^(e),        —(CH₂)_(r)-thienyl substituted with 0-2 R^(e),        —(CH₂)_(r)-thiazolyl substituted with 0-2 R^(e),        —(CH₂)_(r)-imidazolyl substituted with 0-2 R^(e), piperazinyl        substituted with 0-2 R^(e), or —(CH₂)_(r)-pyridinyl substituted        with 0-2 R^(e); and    -   R^(e) is, independently at each occurrence, C₁₋₆ alkyl, F, Cl,        CN, or Bn.

In an eighth embodiment, the present invention includes compounds ofFormula (II), or a stereoisomer, tautomer, pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein:

-   -   ring A is selected from:    -   R^(1d) and R^(1f) are, independently at each occurrence, C₁₋₆        alkyl substituted with 0-2 R^(a), —C(O)OR^(c), —C(O)NR¹²R¹³,        —(CH₂)_(r)-phenyl substituted with 0-3 R^(b),        —(CH₂)_(r)-naphthyl substituted with 0-3 R^(b), —(CH₂)_(r)-5- to        10-membered heterocycle substituted with 0-3 R^(b), wherein said        heterocycle is selected from: thienyl, isoxazolyl, benzothienyl,        and 1,3-benzodioxolyl;    -   R^(a) is, independently at each occurrence, OMe or N(Me)Bn; and    -   R^(b) is, independently at each occurrence, Me, F, Cl, Br,        CH₂OH, CF₃, —CH₂NMe₂, —CH₂N(Me)Bn, CN, NO₂, —SO₂Me, 2-CH₂NH₂-Ph,        —(CH₂)_(r)—C₃₋₆ cycloalkyl, —(CH₂)_(r)-phenyl,        —(CH₂)_(r)-pyrrolidinyl, —(CH₂)_(r)-tetrazolyl,        —(CH₂)_(r)-piperidinyl, —(CH₂)_(r)-azepanyl,        —(CH₂)_(r)-morpholinyl, —(CH₂)_(r)-piperazinyl,        —(CH₂)_(r)-(4-Bn-piperazinyl), or        —(CH₂)_(r)-tetrahydroisoquinolinyl.

In a ninth embodiment, the present invention includes compounds ofFormula (II), or a stereoisomer, tautomer, pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein:

-   -   ring A is selected from:    -   R^(1d) and R^(1e) are, independently at each occurrence, CN,        —C(O)OR^(c), NR¹²R¹³, or —C(O)NR¹²R¹³, C₁₋₆ alkyl substituted        with 0-2 R^(a), or —(CH₂)_(r)-phenyl substituted with 0-3 R^(b);    -   R¹¹ is, independently at each occurrence, H, C₁₋₆ alkyl        substituted with 1-5 fluorine, —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³,        C₁₋₆ alkyl substituted with 0-2 R^(a), C₂₋₆ alkenyl substituted        with 0-2 R^(a), —(CH₂)_(r)—C₃₋₆ cycloalkyl substituted with 0-2        R^(b), —(CH₂)_(r)-phenyl substituted with 0-3 R^(b),        —CHMe-phenyl substituted with 0-3 R^(b), or —(CH₂)_(r)-5- to        10-membered heterocycle substituted with 0-3 R^(b), wherein said        heterocycle is selected from: furanyl, thienyl, thiazolyl,        pyridinyl, and indolyl;    -   R^(a) is, independently at each occurrence, OR^(c), SR^(c),        —C(O)OR^(c), —(CR^(f)R^(f))_(r)NR¹²R¹³,        —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³, or C₁₋₄ alkyl substituted with        1-5 fluorine; and    -   R^(b) is, independently at each occurrence, C₁₋₄ alkyl, C₁₋₄        alkoxyl, F, Cl, Br, CF₃, —OCF₃, CN, —(CR^(f)R^(f))_(r)NR¹²R¹³,        —CH₂NMe₂, NO₂, or —SO₂Me.

In a tenth embodiment, the present invention provides compounds ofFormula (IIa):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein:

-   -   R^(1a) is H, Me, Et, i-Pr, neopentyl, vinyl, 1-Me-vinyl,        cyclopentyl, 1-cyclopentenyl, cyclohexyl, 1-cyclohexenyl, Br,        CF₃, —C(NH₂)═N(OH), —CH₂OH, —(CH₂)₂OH, —CH₂OMe, COMe, CO₂H,        CO₂Me, CO₂Et, —CH₂CO₂H, —CH₂CO₂Et, CN, —N(Me)Et, —N(CH₂CH₂OMe)₂,        —N(Me)CH₂CH₂NMe₂, —N(Me)CH₂CH₂CH₂NMe₂, —CH₂NHEt, —CH₂NH(t-Bu),        —CH₂NH-neopentyl, —CH₂NHBn, —CH₂N(Me)Et, —CH₂N(Me)Pr,        —CH₂N(Me)(i-Bu), —CH₂N(Me)(t-Bu), —CH₂N(Me)cyclohexyl,        —CH₂N(Me)Ph, —CH₂N(Me)Bn, —CH₂N(i-Pr)Bn, —CH₂N(t-Bu)Bn,        —CH₂N(Me)CH(Me)Ph, —CH₂N(Me)(CH₂)₂Ph, —CH₂N(Me)(CH₂)₃Ph,        —CH₂N(Me)(CH₂-pyridin-3-yl), —CONH₂, —CONHMe, —CONHEt, —CONHPr,        —CONH-neopentyl, —CONHPh, —CONHBn, —CONH(CH₂-pyridin-2-yl),        —CONH(CH₂-pyridin-3-yl), —CONH(CH₂CH₂-pyridin-3-yl), —CH₂CONHBn,        —CON(Me)₂, —CON(Me)Et, —CON(Me)Pr, —CON(Me)(t-Bu), —CON(Me)Bn,        —CON(Me)(CH₂)₂OH, —CON(Me)(CH₂)₂Ph, —CON(Me)(CH₂)₃Ph,        —CON(Me)(CH₂-pyridin-3-yl), —CH₂CON(Me)Et, —SO₂-morpholin-4-yl,        —SO₂NHEt, —SO₂NHBn, —SO₂N(Me)Et, —SO₂N(Me)Bn, —SO₂N(Bn)₂, Ph,        2-Me-Ph, 3-Me-Ph, 4-Me-Ph, 4-(i-Pr)-Ph, 4-(t-Bu)-Ph, 2-F-Ph,        3-CF₃-Ph, 4-CF₃-Ph, 2-OH-Ph, 3-OH-Ph, 4-OH-Ph, 4-CH₂OH-Ph,        3-(—CH₂CH₂CH₂OH)-Ph, 4-(—CH₂CH₂CH₂OH)-Ph, 3-OMe-Ph, 4-OMe-Ph,        3-OCF₃-Ph, 4-OCF₃-Ph, 2-CH₂OMe-Ph, 3-NMe₂-Ph, 4-NMe₂-Ph,        2-(—CH₂NHMe)-Ph, 3-(—CH₂NHMe)-Ph, 4-(—CH₂NHMe)-Ph,        2-(—CH₂NHBn)-Ph, 3-(—CH₂NHBn)-Ph, 4-(—CH₂NHBn)-Ph,        2-(—CH₂NMe₂)-Ph, 3-(—CH₂NMe₂)-Ph, 4-(—CH₂NMe₂)-Ph,        2-(—CH₂N(Me)Bn)-Ph, 3-(—CH₂N(Me)Bn)-Ph, 4-(—CH₂N(Me)Bn)-Ph,        3-(—CH₂CH₂CH₂N(Me)Et)-Ph, 4-(—CH₂CH₂CH₂N(Me)Et)-Ph, 3-CO₂H-Ph,        4-CO₂H-Ph, 3-CO₂Me-Ph, 4-CO₂Me-Ph, 3-(—CH₂CH₂CO₂H)-Ph,        4-(—CH₂CH₂CO₂H)-Ph, 3-(—CH₂CH₂CO₂Me)-Ph, 2-CN-Ph, 3-CN-Ph,        4-CN-Ph, 4-SO₂Me-Ph, 2-OBn-Ph, 3-OBn-Ph, 4-OBn-Ph,        3-(—OCH₂C(Me)₂CH₂NMe₂)-Ph, 4-(—OCH₂C(Me)₂CH₂NMe₂)-Ph,        2,4-diF-Ph, 3,5-diF-Ph, 2-F-4-Me-Ph, 2-F-4-OMe-Ph, 3-F-4-OMe-Ph,        2-(—CH₂NMe₂)-4-OMe-Ph, 3-(—CH₂NHMe)-4-OMe-Ph,        2-(—CH₂NHBn)-4-OMe-Ph, 2-(—CH₂N(Me)Bn)-4-OMe-Ph,        3,4,5-triOMe-Ph, pyrrolidin-1-yl, 2-(CH₂OMe)-pyrrolidin-1-yl,        3-(—N(Me)COMe)-pyrrolidin-1-yl, furan-3-yl, imidazol-1-yl,        3-Me-1,2,4-oxadiazol-5-yl, 5-Me-1,2,4-oxadiazol-3-yl,        3-Ph-1,2,4-oxadiazol-5-yl, 1H-tetrazol-5-yl,        1H-1,2,4-triazol-3-yl, 1-(i-Pr)-1,2,4-triazol-3-yl,        piperidin-1-yl, 4-OH-piperidin-1-yl, 3-OMe-piperidin-1-yl,        4-CH₂OH-piperidin-1-yl, 2-(—CH₂CH₂OH)-piperidin-1-yl,        4-(—CH₂CH₂OH)-piperidin-1-yl, 2-(—CH₂NMe₂)-piperidin-1-yl,        2-CO₂Et-piperidin-1-yl, 3-CO₂Et-piperidin-1-yl,        4-CO₂Et-piperidin-1-yl, 3-CONH₂-piperidin-1-yl,        4-CONH₂-piperidin-1-yl, 3-CON(Et)₂-piperidin-1-yl,        —N(Me)(1-Me-piperidin-4-yl), 4-(pyrrolidin-1-yl)-piperidin-1-yl,        piperazin-1-yl, 4-Me-piperazin-1-yl, 4-Et-piperazin-1-yl,        4-i-Pr-piperazin-1-yl, 4-(—CH₂CH₂OH)-piperazin-1-yl,        4-(—CH₂CH₂OCH₂CH₂OH)-piperazin-1-yl, 4-COMe-piperazin-1-yl,        4-CO₂Et-piperazin-1-yl, 4-Bn-piperazin-1-yl, pyridin-3-yl,        pyridin-4-yl, —N(Me)(1-Me-pyrrolidin-3-yl),        —N(Me)-CH₂-pyridin-3-yl, —N(Me)-CH₂-pyridin-4-yl,        morpholin-4-yl, —CH₂-morpholin-4-yl, —CO-morpholin-4-yl,        2-OMe-pyrimidin-5-yl, 1,3-benzodioxol-4-yl,    -   R^(1b) is H, Me, Et, i-Pr, i-Bu, t-Bu, neopentyl, cyclopropyl,        cyclobutyl, CH₂OH, —C(Me)₂CH₂OH, —C(Me)₂(CH₂)₂OH, —CH₂OMe,        —CH₂OEt, CH₂O(i-Bu), —CH₂O(CH₂)₂OMe, CO₂Et, —CH₂CO₂(i-Pr),        —(CH₂)₂CO₂Me, —(CH₂)₂CO₂Et, —C(Me)₂CH₂CO-morpholin-4-yl,        —C(Me)₂CO₂H, —C(Me)₂CO₂Me, —C(Me)₂CH₂CO₂H, —C(Me)₂CH₂CO₂Et,        —C(Me)₂(CH₂)₂CO₂H, —C(Me)₂(CH₂)₃CO₂H, CN, —C(Me)₂CH₂CN, CF₃,        —CH₂CF₃, —CF₂CF₃, —CH(i-Bu)NH₂, —CH₂NMe₂, —C(Me)₂CH₂N(Me)Et,        —C(Me)₂(CH₂)₂N(Me)Et, —C(Me)₂(CH₂)₂N(Me)(i-Bu), —CH₂OCH₂CH₂NEt₂,        —CONHMe, —CONHEt, —CONHPr, —CONH(t-Bu), —CONH-neopentyl,        —CONHPh, —CONHBn, —CONMe₂, —CON(Me)(t-Bu), —CON(Me)Bn,        —C(Me)₂CON(Me)Et, —C(Me)₂CH₂CONH₂, —C(Me)₂CH₂CONHEt,        —C(Me)₂CH₂CONHBn, —C(Me)₂CH₂CON(Me)Et, —C(Me)₂CH₂CON(Me)(i-Bu),        —C(Me)₂CH₂CON(Me)Bn, —CH(i-Bu)NHCO₂(t-Bu), Ph, 4-Me-Ph, 3-F-Ph,        2-CH₂OH-Ph, 3-CH₂OH-Ph, 4-CH₂OH-Ph, 2-OMe-Ph, 3-OMe-Ph,        4-OMe-Ph, 2-(CH₂NHEt)-Ph, 2-(CH₂NHBn)-Ph, 2-(CH₂NMe₂)-Ph,        2-(CH₂N(Me)Et)-Ph, 2-(CH₂N(Me)Bn)-Ph, 3-(CH₂N(Me)Bn)-Ph,        4-(CH₂N(Me)Bn)-Ph, 2-CO₂Et-Ph, 4-CF₃-Ph, 4-OCF₃-Ph, 4-CN-Ph,        2-NO₂-Ph, 3-NO₂-Ph, 4-NO₂-Ph, —C(Me)₂(CH₂)₂(pyrrolidin-1-yl),        —CH₂OCH₂(1-Me-piperidin-3-yl), —CH₂OCH₂(1-Me-piperidin-4-yl),        alternatively,    -   R⁷ is H, Br, CN, NH₂, NHMe, NMe₂, or —NH(4-OMe-Ph);    -   R⁸ is H, Br, CN, NHMe, NMe₂, or —N(Me)(4-OMe-Ph); and    -   R¹¹ is H, Pr, i-Pr, Bu, i-Bu, isopentyl, —CH₂CH(Me)Et,        —CH₂CH(Et)₂, —CH₂CH₂CMe₃, cyclopropylmethyl, cyclopentylmethyl,        —(CH₂)₂OH, Bn, —COMe, —COPh, —COBn, —SO₂Me, —SO₂Ph, —SO₂Bn, Bn,        2-Me-Bn, 3-Me-Bn, 3-OH-Bn, 4-OH-Bn, 2-OMe-Bn, 3-OMe-Bn,        4-OMe-Bn, 2-F-Bn, 3-OCF₃-Bn, 3-CN-Bn, 4-CN-Bn, phenethyl,        2-furanylmethyl, 3-furanylmethyl, 3-pyridylmethyl, or        4-pyridylmethyl.

In an eleventh embodiment, the present invention includes compounds ofFormula (IIa), or a stereoisomer, tautomer, pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein:

-   -   R⁶ is 2-t-Bu-Ph;    -   R⁷ is H; and    -   R⁸ is H.

In a twelfth embodiment, the present invention provides compounds ofFormula (IIb):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein:

-   -   R^(1c) is H, i-Pr, t-Bu, neopentyl, cyclopropyl,        1-Ph-cyclopropyl, cyclobutyl, cycopentyl, cyclohexyl,        4-NHBn-cyclohexyl, 4-N(Me)Bn-cyclohexyl, —CH₂OBn,        —CH₂O(CH₂)₂OMe, CO₂H, CO₂Et, —C(Me)₂(CH₂)₂CO₂Me, —CH₂N(Me)Bn,        —(CH₂)₃N(Me)Bn, —C(Me)₂(CH₂)₃N(Me)Bn, —CON(Me)Bn,        —C(Me)₂CH₂CON(Me)Bn, —C(Me)₂(CH₂)₂CON(Me)Bn, Ph, phenethyl,        3-Me-Ph, 4-Me-Ph, 4-t-Bu-Ph, 3-OH-Ph, 2-OMe-Ph, 4-OMe-Ph,        4-F-Ph, 2-Cl-Ph, 3-Cl-Ph, 4-CF₃-Ph, 3-OCF₃-Ph, 4-OCF₃-Ph,        4-CN-Ph, 3-NMe₂-Ph, 4-NMe₂-Ph, 2-CH₂NMe₂-Ph, 3-CH₂NMe₂-Ph,        4-CH₂NMe₂-Ph, 4-NO₂-Ph, 4-Ph-Ph, 3,5-diCl-Ph,        4-(imidazol-1-yl)-Ph, 3-(4-Bn-piperazin-1-yl)-Ph,        4-(4-Bn-piperazin-1-yl)-Ph, 4-F-Bn, 4-OMe-Bn, 4-NMe₂-Bn,        naphth-2-yl, 1-Bn-pyrrolidin-3-yl, thien-2-yl, —CH₂-thien-2-yl,        1-Me-pyrrol-2-yl, 2,5-diMe-furan-3-yl, isoxazol-5-yl,        pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,        1-neohexyl-4-Me-piperidin-4-yl,        1-(CH₂-cyclohexyl)-4-Me-piperidin-4-yl, 2-Ph-piperidin-4-yl,        1-Me-2-Ph-piperidin-4-yl, 1-Bn-piperidin-3-yl,        1-Bn-piperidin-4-yl, 1-Bn-4-Me-piperidin-4-yl,        1-(2-Cl-Bn)-piperidin-4-yl, 1-(2-Cl-Bn)-4-Me-piperidin-4-yl,        1-(2-CN-Bn)-4-Me-piperidin-4-yl,        1-(3-CN-Bn)-4-Me-piperidin-4-yl,        1-(4-CN-Bn)-4-Me-piperidin-4-yl,        1-(2,4-diF-Bn)-4-Me-piperidin-4-yl,        1-(2,5-diF-Bn)-4-Me-piperidin-4-yl,        1-(2,6-diCl-Bn)-4-Me-piperidin-4-yl,        1-(CH₂-naphth-1-yl)-4-Me-piperidin-4-yl,        1-(CH₂-furan-3-yl)-4-Me-piperidin-4-yl,        1-(CH₂-thien-2-yl)-4-Me-piperidin-4-yl,        1-(CH₂-thiazol-2-yl)-4-Me-piperidyin-4-yl,        1-(CH₂-pyrid-2-yl)-4-Me-piperid-4-yl,        1-(CH₂-pyrid-3-yl)-4-Me-piperid-4-yl,        1-(1-Bn-piperid-4-yl)-piperid-4-yl, —CH₂-(4-Bn-piperazin-1-yl),        —(CH₂)₃-(4-Bn-piperazin-1-yl),        —C(Me)2(CH₂)₃-(4-Bn-piperazin-1-yl),        —C(Me)₂(CH₂)₂CO(4-Bn-piperazin-1-yl),    -   R⁵ is 2-t-Bu-Ph, 2-Br-Ph, 2-CO₂Me-Ph, 3-CO₂Et-Ph,

In a thirteenth embodiment, the present invention provides compounds ofFormula (IIc):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein:

-   -   R^(1c) is Me, i-Pr, t-Bu, cyclopropyl, Br, CF₃, —CH₂OPh,        —CH₂O(4-t-Bu-Ph), —CH₂O(2-Cl-Ph), —CH₂O(4-Cl-Ph), —CH₂SPh,        —CH₂N(Me)Bn, Ph, 4-Me-Ph, 4-t-Bu-Ph, 3-OH-Ph, 4-OMe-Ph, 2-F-Ph,        3-F-Ph, 4-Cl-Ph, 3-CF₃-Ph, 4-CF₃-Ph, 3-NO₂-Ph, 4-SO₂Me-Ph,        3-Cl-4-F-Ph, 3,4-diOMe-Ph, 3,5-diOMe-Ph, 3,5-diCl-Ph,        2,6-diCl-Bn, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,        2,6-diCl-pyridin-4-yl, furan-3-yl, thien-2-yl, pyrazin-2-yl,        —CH₂-1-(1,2,4-triazol-1-yl), 1-Bn-piperidin-4-yl,        —CH₂-piperidin-1-yl, —CH₂-4-Bn-piperazin-1-yl,        benzo[b]thien-3-yl, or        and    -   R⁵ is 2-t-Bu-Ph, 2-Br-Ph, 2-CO₂Me-Ph, 3-CO₂Et-Ph,

In a fourteenth embodiment, the present invention provides compounds ofFormula (IId₁) or Formula (IId₂):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein:

-   -   R^(1d) is, independently at each occurrence, —CH(OMe)₂,        —CH₂N(Me)Bn, CO₂Et, —CON(Me)Bn, Ph, 2-F-Ph, 3-F-Ph, 2-Cl-Ph,        3-Cl-Ph, 3-CH₂OH-Ph, 3-CH₂NMe₂-Ph, 4-CF₃-Ph, 3-CN-Ph, 4-CN-Ph,        3-NO₂-Ph, 4-NO₂-Ph, 4-SO₂Me-Ph, 4-cyclohexyl-Ph, 4-Ph-Ph,        3-CH₂N(Me)Bn-Ph, 3-(CH₂-piperidin-1-yl)-Ph,        3-(CH₂-morpholin-4-yl)-Ph, 3-(CH₂-piperazin-1-yl)-Ph,        3-(CH₂-(4-Me-piperazin-1-yl))-Ph, 2,4-diMe-Ph, 3-Me-4-Cl-Ph,        3,4-diCl-Ph, 2-F-4-Br-Ph, 3-NO₂-4-Cl-Ph,        2-F-4-(2-CH₂NMe₂-Ph)-Ph, 2-F-4-(pyrrolidin-1-yl)-Ph,        4-(1H-tetrazol-5-yl)-Ph, 2-F-4-(piperidin-1-yl)-Ph,        2-F-4-(1-azepanyl)-Ph, 2-F-4-(4-Bn-piperazin-1-yl)-Ph,        2-F-4-Cl-5-Me-Ph, naphth-2-yl, 3-Ph-isoxazol-5-yl,        3-Ph-5-Me-isoxazol-4-yl, 5-Ph-thien-2-yl, pyridin-3-yl,        pyridin-4-yl, benzo[b]thien-3-yl, 1,3-benzodioxol-4-yl, or        3-(CH₂-1,2,3,4-tetrahydroisoquinolin-2-yl)-Ph.

In a fifteenth embodiment, the present invention provides compounds ofFormula (IIe₁) or Formula (IIe₂):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein:

-   -   R^(h) is, independently at each occurrence, CN, CO₂Et, CONMe₂,        Ph, 2-F-Ph, or 4-CF₃-Ph; and    -   R¹¹ is, independently at each occurrence, H, Me, n-Bu, neohexyl,        —CH₂CH═C(Me)₂, —(CH₂)₂OMe, —(CH₂)₂SMe, —(CH₂)₂SEt,        —(CH₂)₂S(i-Pr), —(CH₂)₃SMe, —(CH₂)₃N(Me)₂, —(CH₂)₂O(CH₂)₂Cl,        —(CH₂)₂O(4-Cl-Ph), —CH₂-cyclopropyl, Ph, Bn, 2-Cl-Bn, 3-Cl-Bn,        2-Br-Bn, 4-Br-Bn, 4-CF₃-Bn, 4-SMe-Bn, 2-F-6-Cl-Bn, 2-Cl-4-F-Bn,        2-F-4-Br-Bn, 3,5-diCl-Bn, —CHMe-Ph, phenethyl, 4-Cl-phenethyl,        —CH₂-thien-2-yl, —(CH₂)₂-thien-2-yl, —(CH₂)₂-thien-3-yl,        —(CH₂)₂-(4-Me-thiazol-5-yl), —CHMe-furan-2-yl,        —(CH₂)₂-pyridin-2-yl, —(CH₂)₂-pyridin-4-yl, or        —(CH₂)₂-indol-3-yl.

In a sixteenth embodiment, the present invention includes compounds ofFormula (II), or a stereoisomer, tautomer, pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein:

-   -   R⁵ is a phenyl substituted with 1-2 R^(5a);    -   R^(5a) is, independently at each occurrence, F, Cl, Br, I, CN,        —C(Me)₂CN, CF₃, —CF₂CF₃, OCF₃, —OCF₂CF₂H, —OCF₂CF₃, C₁₋₈ alkyl,        C₂₋₈ alkenyl, OH, C₁₋₄ alkyloxy, SMe, S(i-Pr), —C(Me)₂OMe,        —C(Me)₂OEt, —C(Me)₂OPr, —CHMeO(CH₂)₂OMe, —C(Me)₂OBu,        —C(Me)₂O(CH₂)₂OMe, —C(Me)(OMe)CH₂OMe, —C(Me)₂O(CH₂)₂N(i-Bu)₂,        —C(Me)₂O(CH₂)₂S(i-Bu), —C(Me)₂O(CH₂)₂S(O)(i-Bu),        —C(Me)₂O(CH₂)₂S(furan-2-ylmethyl),        —C(Me)₂O(CH₂)₂S(pyridin-2-yl),        —C(Me)₂O(CH₂)₂S(O)₂(pyridin-2-yl), —C(Me)₂CH₂OSi(Me)₂(t-Bu),        —C(Me)₂O(CH₂)₂Si(Me)₂(t-Bu), —C(Et)₂OH, —C(Pr)₂OH,        —C(CH₂CH═CH₂)₂OH, —C(CH₂CH═CH₂)₂OMe, —C(Et)₂OMe, —C(Et)₂OEt,        —C(Et)₂OPr, COMe, COPh, CO₂Me, CO₂Et, —NH(i-Bu),        —CH═CHCO₂(t-Bu), —OCH₂CO₂(t-Bu), C₃₋₇ cycloalkyl, C₃₋₇        cycloalkenyl, Ph, Bn, naphthyl, 1-pyrrolidinyl, 5-isoxazolyl,        N-morpholinyl, 1-piperidinyl, —SiMe₃,    -   alternatively, R⁵ is:

In a seventeenth embodiment, the present invention includes compounds ofFormula (II), or a stereoisomer, tautomer, pharmaceutically acceptablesalt, solvate, or prodrug thereof, wherein:

-   -   R⁵ is 2-i-Pr-Ph, 2-t-Bu-Ph, 2-Br-Ph, 2-OCF₃-Ph, 2-CO₂Me-Ph,        3-CO₂Et-Ph,

In an eighteenth embodiment, the present invention provides a compoundselected from the exemplified examples or a stereoisomer, tautomer,pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, the present invention includes compounds ofFormula (II):

or a stereoisomer or pharmaceutically acceptable salts, solvates, orprodrugs thereof, wherein:

-   -   ring A is selected from:    -   alternatively, ring A is substituted with 0-3 R¹ and selected        from:    -   R¹, R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) are,        independently at each occurrence, C₁₋₆ alkyl substituted with        0-2 R^(a), Br, CN, CF₃, —CF₂CF₃, COH, —CH(═NOH), —C(O)OR^(c),        NR¹²R¹³, —C(O)NR¹²R¹³, —CON(Me)(CH₂)₂OH, —CO-morpholin-4-yl,        —SO₂-morpholin-4-yl, —S(O)_(p)NR¹²R¹³, —(CH₂)_(r)—C₃₋₆        cycloalkyl substituted with 0-2 R^(b), —(CH₂)_(r)-adamantyl        substituted with 0-2 R^(b), —(CH₂)_(r)-phenyl substituted with        0-4 R^(b), —(CH₂)_(r)-naphthyl substituted with 0-4 R^(b),        —(CH₂)_(r)-5- to 10-membered heterocycle substituted with 0-4        R^(b) and selected from: azetidinyl, pyrrolidinyl, furanyl,        thienyl, pyrrolyl, isoxazolyl, triazolyl, tetrazolyl, pyridinyl,        pyrazinyl, pyrimidinyl, piperdinyl, morpholinyl, piperazinyl,        1,3-benzodioxolyl, benzothienyl, isoindolinyl,        tetrahydroisoquinolyl, and        alternatively, two R¹s on two adjacent carbon atoms are combined        with the carbon atoms to which they attached, form a 5- to        6-membered carbocycle or heterocycle comprising: carbon atoms        and 0-3 additional heteroatoms selected from N, NR¹¹, O, and        S(O)_(p), 0-2 carbonyl, and 0-1 additional double bond, wherein        said carbocycle or heterocycle is substituted with 0-3 R^(b);    -   R⁵ is 2-i-Pr-Ph, 2-t-Bu-Ph, 2-Br-Ph, 2-OCF₃-Ph, 3-CO₂Et-Ph,    -   R⁷ is H, Br, CN, NH₂, NMe₂, or —NH(4-OMe-Ph);    -   R⁸ is H, Br, CN, NMe₂, or —N(Me)(4-OMe-Ph);    -   R¹¹ is, independently at each occurrence, H, —COPh, —COBn,        —SO₂Me, —SO₂Ph, —SO₂Bn, C₁₋₄ alkyl substituted with 0-2 R^(a),        —(CH₂)_(r)-phenyl substituted with 0-3 R^(b), —CHMe-phenyl        substituted with 0-3 R^(b), or —(CH₂)_(r)-5- to 10-membered        heterocycle substituted with 0-3 R^(b) and selected from:        furanyl, thienyl, thiazolyl, pyridinyl, and indolyl;    -   R¹² is, independently at each occurrence, H, C₁₋₆ alkyl,        —(CH₂)_(r)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, —(CH₂)_(r)-5- to        6-membered heterocycle selected from pyrrolidinyl, furanyl,        thienyl, pyrrolyl, isoxazolyl, triazolyl, tetrazolyl, pyridinyl,        pyrazinyl, pyrimidinyl, piperdinyl, morpholinyl, and        piperazinyl;    -   R¹³ is, independently at each occurrence, H, C₁₋₆ alkyl, or        —(CH₂)_(n)-phenyl;    -   R^(a) is, independently at each occurrence, OH, OR^(c), SR^(c),        —C(O)OR^(c), NR¹²R¹³, —C(O)NR¹²R¹³, or —CO-4-morpholin-4-yl;    -   R^(b) is, independently at each occurrence, C₁₋₆ alkyl, C₁₋₄        alkoxyl, F, Cl, Br, CF₃, —OCF₃, —CH₂OH, OH, OMe, —CH₂OMe,        —(CH₂)_(r)—C(O)OR^(c), —(CH₂)_(r)—NR¹²R¹³,        —(CH₂)_(r)—C(O)NR¹²R¹³, CN, —OCH₂C(Me)₂CH₂NMe₂, NO₂, —SO₂Me,        OBn, —(CH₂)_(r)—C₃₋₆ cycloalkyl, —(CH₂)_(r)-phenyl substituted        with 0-2 R^(e), —(CH₂)_(r)-naphthyl substituted with 0-3 R^(e),        —(CH₂)_(r)-5- to 10-membered heterocycle substituted with 0-4        0-4 R^(e) and selected from: thienyl, thiazolyl, imidazolyl,        tetrazolyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl,        piperazinyl, pyridinyl or tetrahydroisoquinolinyl;    -   R^(c) is, independently at each occurrence, H, C₁₋₆ alkyl        substituted with 0-2 R^(e), or —(CH₂)_(r)-phenyl substituted        with 0-2 R^(e);    -   R^(e) is, independently at each occurrence, C₁₋₄ alkyl, OMe, F,        Cl, —CH₂NH₂, CN, Ph, or Bn;    -   n, at each occurrence, is selected from 0, 1, 2, 3, and 4;    -   p, at each occurrence, is selected from 0, 1, and 2; and    -   r, at each occurrence, is selected from 0, 1, 2, 3, and 4.

In another embodiment, the present invention includes compounds ofFormula (II), wherein:

-   -   ring A is    -   R^(1a) and R^(1b), independently at each occurrence, H, C₁₋₆        alkyl substituted with 0-2 R^(a), Br, CN, CF₃, —CF₂CF₃,        —C(O)OR^(c), —C(O)NR¹²R¹³, —CON(Me)(CH₂)₂OH,        —SO₂-morpholin-4-yl, —S(O)_(p)NR¹²R¹³, —CO-(4-morpholinyl),        —(CH₂)_(r)-phenyl substituted with 0-3 R^(b); —(CH₂)_(r)-5- to        10-membered heterocycle substituted with 0-3 R^(b)and selected        from: pyrrolidinyl, furanyl, triazolyl, tetrazolyl, piperidinyl,        morpholinyl, piperazinyl, pyridyl, pyrimidinyl,        1,3-benzodioxolyl, isoindolinyl, tetrahydroisoquinolinyl, and    -   alternatively, ring A is    -   R¹¹ is H, C₁₋₄ alkyl, —(CH₂)₂OH, Bn, —COPh, —COBn, —SO₂Me,        —SO₂Ph, or —SO₂Bn;    -   R^(a) is, independently at each occurrence, OH, OMe,        —C(O)OR^(c), NR¹²R¹³, —C(O)NR¹²R¹³, or —CO(4-morpholinyl); and    -   R^(b) is, independently at each occurrence, C₁₋₄ alkyl, F, CF₃,        —OCF₃, —CH₂OH, OH, OMe, —CH₂OMe, —OCH₂C(Me)₂CH₂NMe₂, CO₂Me,        CO₂Et, CN, —CH₂NHMe, —CH₂NHEt, —CH₂NHBn, —CH₂NMe₂, —CH₂N(Me)Et,        —CH₂N(Me)Bn, NO₂, —SO₂Me, or OBn.

In another embodiment, the present invention includes the compounds ofFormula (IIa), wherein:

-   -   R^(1a) is H, Me, Br, —CH₂OH, —(CH₂)₂OH, —CH₂OMe, CO₂H, CO₂Me,        CO₂Et, —CH₂CO₂H, —CH₂CO₂Et, CN, —CH₂NHEt, —CH₂NH(t-Bu),        —CH₂NH-neopentyl, —CH₂NHBn, —CH₂N(Me)Et, —CH₂N(Me)Pr,        —CH₂N(Me)(t-Bu), —CH₂N(Me)cyclohexyl, —CH₂N(Me)Ph, —CH₂N(Me)Bn,        —CH₂N(i-Pr)Bn, —CH₂N(t-Bu)Bn, —CH₂N(Me)CH(Me)Ph,        —CH₂N(Me)(CH₂)₂Ph, —CH₂N(Me)(CH₂)₃Ph,        —CH₂N(Me)(CH₂-pyridin-3-yl), —CONH₂, —CONHMe, —CONHEt, —CONHPr,        —CONH-neopentyl, —CONHPh, —CONHBn, —CONH(CH₂-pyridin-2-yl),        —CONH(CH₂-pyridin-3-yl), —CONH(CH₂CH₂-pyridin-3-yl), —CH₂CONHBn,        —CON(Me)₂, —CON(Me)Et, —CON(Me)Pr, —CON(Me)(t-Bu), —CON(Me)Bn,        —CON(Me)(CH₂)₂OH, —CON(Me)(CH₂)₂Ph, —CON(Me)(CH₂)₃Ph,        —CON(Me)(CH₂-pyridin-3-yl), —CH₂CON(Me)Et, —SO₂-morpholin-4-yl,        —SO₂NHEt, —SO₂NHBn, —SO₂N(Me)Et, —SO₂N(Me)Bn, —SO₂N(Bn)₂, Ph,        2-Me-Ph, 3-Me-Ph, 4-Me-Ph, 3-CF₃-Ph, 4-CF₃-Ph, 4-CH₂OH-Ph,        3-OH-Ph, 4-OH-Ph, 3-OMe-Ph, 4-OMe-Ph, 3-OCF₃-Ph, 4-OCF₃-Ph,        2-CH₂OMe-Ph, 2-(—CH₂NMe₂)-Ph, 2-(—CH₂NHMe)-Ph, 3-(—CH₂NHMe)-Ph,        4-(—CH₂NHMe)-Ph, 2-(—CH₂NHBn)-Ph, 3-(—CH₂NHBn)-Ph,        4-(—CH₂NHBn)-Ph, 3-(—CH₂NMe₂)-Ph, 4-(—CH₂NMe₂)-Ph,        2-(—CH₂N(Me)Bn)-Ph, 3-(—CH₂N(Me)Bn)-Ph, 4-(—CH₂N(Me)Bn)-Ph,        3-CO₂Me-Ph, 4-CO₂Me-Ph, 2-CN-Ph, 3-CN-Ph, 4-CN-Ph, 4-SO₂Me-Ph,        3-OBn-Ph, 4-OBn-Ph, 3-(—OCH₂C(Me)₂CH₂NMe₂)-Ph,        4-(—OCH₂C(Me)₂CH₂NMe₂)-Ph, 2,4-diF-Ph, 3,5-diF-Ph, 3-F-4-OMe-Ph,        2-(—CH₂NMe₂)-4-OMe-Ph, 3-(—CH₂NHMe)-4-OMe-Ph,        2-(—CH₂NHBn)-4-OMe-Ph, 2-(—CH₂N(Me)Bn)-4-OMe-Ph,        3,4,5-triOMe-Ph, pyrrolidin-1-yl, furan-3-yl, 1H-tetrazol-5-yl,        1H-1,2,4-triazol-3-yl, piperidin-1-yl,        —N(Me)(1-Me-piperidin-4-yl), 4-(pyrrolidin-1-yl)-piperidin-1-yl,        piperazin-1-yl, 4-Me-piperazin-1-yl, 4-Et-piperazin-1-yl,        4-i-Pr-piperazin-1-yl, 4-Bn-piperazin-1-yl, pyridin-4-yl,        —N(Me)-CH₂-pyridin-3-yl, —N(Me)-CH₂-pyridin-4-yl,        —CH₂-morpholin-4-yl, —CO-morpholin-4-yl, 2-OMe-pyrimidin-5-yl,        1,3-benzodioxol-4-yl,    -   R^(1b) is H, Me, Et, t-Bu, —C(Me)₂(CH₂)₂OH, CO₂Et,        —CH₂CO₂(i-Pr), —C(Me)₂CH₂CO-morpholin-4-yl, —C(Me)₂CH₂CO₂Et, CN,        CF₃, —CF₂CF₃, —CH(i-Bu)NH₂, —CONHEt, —CONHPr, —CONH(t-Bu),        —CONH-neopentyl, —CONHPh, —CONHBn, —CON(Me)(t-Bu), —CON(Me)Bn,        —C(Me)₂CH₂CONHBn, —C(Me)₂CH₂CON(Me)Et, —C(Me)₂CH₂CON(Me)Bn,        —CH(i-Bu)NHCO₂(t-Bu), Ph, 4-Me-Ph, 3-F-Ph, 2-CH₂OH-Ph,        3-CH₂OH-Ph, 4-CH₂OH-Ph, 2-OMe-Ph, 3-OMe-Ph, 4-OMe-Ph,        2-(CH₂NHEt)-Ph, 2-(CH₂NHBn)-Ph, 2-(CH₂NMe₂)-Ph,        2-(CH₂N(Me)Et)-Ph, 2-(CH₂N(Me)Bn)-Ph, 3-(CH₂N(Me)Bn)-Ph,        4-(CH₂N(Me)Bn)-Ph, 2-CO₂Et-Ph, 4-CF₃-Ph, 4-OCF₃-Ph, 4-CN-Ph,        2-NO₂-Ph, 3-NO₂-Ph, or 4-NO₂-Ph;    -   alternatively,    -   R⁵ is 2-i-Pr-Ph, 2-t-Bu-Ph, or 2-OCF₃-Ph,    -   R⁷ is H, Br, CN, NH₂, NMe₂, or —NH(4-OMe-Ph);    -   R⁸ is H, Br, CN, NMe₂, or —N(Me)(4-OMe-Ph); and    -   R¹¹ is H, Pr, i-Bu, —(CH₂)₂OH, Bn, —COMe, —COPh, —COBn, —SO₂Me,        —SO₂Ph, or —SO₂Bn.

In another embodiment, the present invention includes the compounds ofFormula (Ia), wherein:

-   -   R⁵ is 2-i-Pr-Ph, 2-t-Bu-Ph, 2-Br-Ph, 2-OCF₃-Ph, 2-CO₂Me-Ph,        3-CO₂Et-Ph,

In another embodiment, the present invention includes the compounds ofFormula (Ia), wherein:

-   -   ring A is substituted with 0-3 R¹ and selected from:    -   ring B is    -   R¹ is, independently at each occurrence, Me, Pr, i-Pr, t-Bu,        —CH₂OH, —C(Me)₂(CH₂)₂OH, —CH₂OMe, —CO₂H, —CH₂CO₂H, —CO₂Me,        —CO₂Et, —CH₂CO₂Et, —CH₂CO₂(i-Pr), —C(Me)₂CH₂CO₂Et,        —C(Me)₂(CH₂)₂CO₂Et, —CF₃, —CF₂CF₃, CN, cyclopropyl,        1-Ph-cyclopropyl, 4-NHBn-cyclohexyl, 4-N(Me)Bn-cyclohexyl, Ph,        Bn, 2-F-Ph, 3-F-Ph, 2-Cl-Ph, 4-Cl-Ph, 2-Me-Ph, 3-Me-Ph, 4-Me-Ph,        4-t-Bu-Ph, 2-OMe-Ph, 3-OMe-Ph, 4-OMe-Ph, 3-CF₃-Ph, 4-CF₃-Ph,        4-OCF₃-Ph, 4-CN-Ph, 2-NO₂-Ph, 3-NO₂-Ph, 4-NO₂-Ph, 4-SO₂Me-Ph,        2-F-4-Br-Ph, 3-Cl-4-F-Ph, 3,4-diOMe-Ph, 3,5-diOMe-Ph,        2,6-diCl-Ph, 2-F-4-(2-CH₂NH₂-Ph)-Ph, 2,6-diCl-Bn, —CH₂OPh,        —CH₂O(4-t-Bu-Ph), —CH₂O(2-Cl-Ph), —CH₂O(4-Cl-Ph), —CH(t-Bu)NH₂,        —CH₂NHEt, —CH₂NH-neopentyl, —CH₂NHPh, —CH₂NHBn, —CH₂N(Me)Et,        —CH₂N(Me)Pr, —CH₂N(Me)(t-Bu), —CH₂N(Me)Ph, —CH₂N(Me)-cyclohexyl,        —CH₂N(Me)Bn, —CH₂N(i-Pr)Bn, —CH₂N(t-Bu)Bn, —CH₂N(Me)CH(Me)Ph,        —CH₂N(Me)(CH₂)₂Ph, —CH₂N(Me)(CH₂)₃Ph, —CH₂N(Me)CH₂(3-pyridyl),        —CH(t-Bu)NHCO₂(t-Bu), —CONHPr, —CONH(t-Bu), —CONH-neopentyl,        —CONHPh, —CONHBn, —CON(Me)₂, —CON(Me)Et, —CON(Me)Pr,        —CON(Me)(t-Bu), —CON(Me)Ph, —CON(Me)Bn, —CON(Me)(CH₂)₂Ph,        —CON(Me)(CH₂)₃Ph, —CH₂CONHBn, —C(Me)₂CH₂CONHBn,        —C(Me)₂CH₂CON(Me)Et, —C(Me)₂CH₂CON(Me)Ph,        —C(Me)₂(CH₂)₂CON(Me)Bn, —CON(Me)CH₂(3-pyridyl), 3-furyl,        2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,6-diCl-4-pyridyl,        2-pyrazinyl, —CH₂—(N-morpholinyl), —CO—(N-morpholinyl),        —C(Me)₂CH₂CO—(N-morpholinyl), 1-Bn-4-Me-4-piperidyl,        —NH-(1-(4-t-Bu-Ph)-4-piperidyl), —(CH₂)₃-(4-Bn-piperazinyl),        —C(Me)2(CH₂)₂-CO-(4-Bn-piperazinyl), 3-benzothienyl,    -   alternatively, ring A is substituted with 0-3 R^(b)and selected        from:    -   R⁵ is 2-t-Bu-Ph,    -   R¹¹ is H, Ph, Bn, —COPh, —COBn, —SO₂Me, —SO₂Ph, or —SO₂Bn;    -   R^(b) is Me or Ph;    -   X is NH; and    -   Y is O.

In another embodiment, the present invention includes, inter alia, amethod for treating a thromboembolic disorder, comprising: administeringto a patient in need thereof a therapeutically effective amount of acompound of Formula (I):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein:

-   -   ring A is 5- to 6-membered heteroaryl comprising: carbon atoms        and 1-4 ring heteroatoms selected from O, N, NR¹¹, and S(O)_(p),        wherein said heteroaryl is substituted with 0-4 R¹;    -   ring B is phenyl substituted with 0-4 R⁷, or a 5- to 6-membered        heteroaryl comprising: carbon atoms and 1-4 ring heteroatoms        selected from N, NR¹¹, S(O)_(p), and O, wherein said heteroaryl        is substituted with 0-4 R⁷;    -   X is —(CR¹⁶R¹⁷)_(s)—, —(CR¹⁶R¹⁷)_(r)CR═CR(CR¹⁶R¹⁷)_(r)—,        —(CR¹⁶R¹⁷)_(r)C≡C(CR¹⁶R¹⁷)_(r)—, —(CR¹⁶R¹⁷)_(t)O(CR¹⁶R¹⁷)_(r)—,        —(CR¹⁶R¹⁷)_(t)NR¹⁴(CR¹⁶R¹⁷)_(r)—,        —(CR¹⁶R¹⁷)_(t)C(O)(CR¹⁶R¹⁷)_(r)—,        —(CR¹⁶R¹⁷)_(t)C(O)O(CR¹⁶R¹⁷)_(r)—,        —(CR¹⁶R¹⁷)_(t)OC(O)(CR¹⁶R¹⁷)_(r)—,        —(CR¹⁶R¹⁷)^(t)C(O)NR¹⁴(CR¹⁶R¹⁷)_(r)—,        —(CR¹⁶R¹⁷)_(t)S(CR¹⁶R¹⁷)_(r)—, —(CR¹⁶R¹⁷)_(t)S(O)(CR¹⁶R¹⁷)_(s)—,        —(CR¹⁶R¹⁷)_(t)S(O)₂(CR¹⁶R¹⁷)_(r)—,        —(CR¹⁶R¹⁷)_(t)SO₂NR¹⁴(CR¹⁶R¹⁷)_(r)—, or        —(CR¹⁶R¹⁷)_(t)NR¹⁴SO₂(CR¹⁶R¹⁷)_(r)—;    -   Y is NR¹⁵, O, or S;    -   R¹ is, independently at each occurrence, F, Cl, Br, I, CF₃,        —CF₂CF₃, OCF₃, —OCF₂CF₂H, —OCF₂CF₃, SiMe₃,        —(CR^(f)R^(f))_(r)—OR^(c), SR^(c), CN, NO₂,        —(CR^(f)R^(f))_(r)—NR¹²R¹³, —(CR^(f)R^(f))_(r)—C(O)R^(c),        —(CR^(f)R^(f))_(r)—CO₂R^(c), —(CR^(f)R^(f))_(r)—C(O)NR¹²R¹³,        —C(O)NR¹⁴(CR^(f)R^(f))_(t)N¹²R¹³,        —(CR^(f)R^(f))_(r)—OC(O)NR¹²R¹³,        —(CR^(f)R^(f))_(r)—NR¹⁴C(O)NR¹²R¹³,        —(CR^(f)R^(f))_(r)—NR¹⁴C(O)R^(d),        —(CR^(f)R^(f))_(r)—NR¹⁴C(O)OR^(h),        —NR¹⁴(CR^(f)R^(f))_(n)C(O)R^(d), —NR¹⁴CO(CR^(f)R^(f))_(n)OR^(c),        —(CH₂)_(r)—CR¹³(═NOR^(c)), —(CH₂)_(r)—C(NH₂)(═NOR^(c)),        —S(O)_(p)NR¹²R¹³, —(CR^(f)R^(f))_(r)—NR¹⁴S(O)_(p)NR¹²R¹³,        —NR¹⁴SO₂CF₃, —NR¹⁴S(O)_(p)R^(d), —S(O)₂CF₃, —S(O)R^(d),        —S(O)₂R^(d), —OP(O)(OEt)₂, —O(CH₂)₂OP(O)(OEt)₂,        4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl, C₁₋₈ alkyl substituted        with 0-2 R^(a), C₂₋₈ alkenyl substituted with 0-2 R^(a), C₂₋₈        alkynyl substituted with 0-2 R^(a), —(CR^(f)R^(f))_(r)—C₃₋₁₃        carbocycle substituted with 0-5 R^(b), or —(CR^(f)R^(f))_(r)-5-        to 10-membered heterocycle comprising: carbon atoms and 1-4        heteroatoms selected from N, NR¹¹, O, and S(O)_(p), wherein said        heterocycle is substituted with 0-5 R^(b);    -   alternatively, two R¹s are combined with the carbon atoms to        which they attached, form a 5- to 7-membered carbocycle or        heterocycle comprising: carbon atoms and 0-3 additional        heteroatoms selected from N, NR¹¹, O, and S(O)_(p), 0-2        carbonyls, and 0-2 double bond, wherein said carbocycle or        heterocycle is substituted with 0-4 R^(b);    -   R⁵ is a —(CR^(f)R^(f))_(n)—C₃₋₁₀ carbocycle substituted with 0-5        R^(5a), or a —(CR^(f)R^(f))_(n)-5- to 10-membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from N,        NR¹¹, O, and S(O)_(p), wherein said heterocycle is substituted        with 0-5 R^(5a);    -   R^(5a) is, independently at each occurrence, F, Cl, Br, I,        —(CR^(i)R^(i))_(r)—OR^(c), SR^(c), CN, NO₂, CF₃, —CF₂CF₃, OCF₃,        —OCF₂CF₂H, —OCF₂CF₃, —NR¹²R¹³, —C(O)R^(c), —C(O)OR^(c),        —C(O)NR¹²R¹³, —NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³, —S(O)R^(d),        —S(O)₂R^(d), —Si(Me)₃, Si(C₁₋₄ alkyl)₃, C₁₋₄ haloalkyl, C₁₋₄        haloalkyloxy-, C₁₋₄ alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄        alkyl-C(O)—, C₁₋₄ alkyl-O—C(O)—, C₁₋₄ alkyl-C(O)NH—, C₁₋₈ alkyl        substituted with 0-2 R^(a), C₂₋₈ alkenyl substituted with 0-2        R^(a), C₂₋₈ alkynyl substituted with 0-2 R^(a),        —(CR^(f)R^(f))_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(e),        or —(CR^(f)R^(f))_(r)-5- to 10-membered heterocycle comprising:        carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and        S(O)_(p), wherein said heterocycle is substituted with 0-3        R^(e);    -   alternatively, two R^(5a) groups, together with the atoms to        which they are attached, form a 5- to 7-membered carbocyclic or        heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms        selected from N, NR¹¹, O, and S(O)_(p), 0-1 carbonyl and 0-3        double bonds, wherein said carbocyclic or heterocyclic ring is        substituted with 0-3 R^(e);    -   R⁷ is, independently at each occurrence, H, F, Cl, Br, I, OCF₃,        CF₃, OR^(c), SR^(c), CN, NO₂, —NR¹²R¹³, —C(O)R^(c), —C(O)OR^(c),        —C(O)NR¹²R¹³, —NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³, —S(O)R^(d),        —S(O)₂R^(d), C₁₋₈ alkyl substituted with 0-2 R^(a), C₂₋₈ alkenyl        substituted with 0-2 R^(a), C₂₋₈ alkynyl substituted with 0-2        R^(a), —(CR^(f)R^(f))_(r)—C₃₋₁₀ carbocycle substituted with 0-3        R^(b), or —(CR^(f)R^(f))_(r)-5- to 10-membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from N,        NR^(7b), O, and S(O)_(p), wherein said heterocycle is        substituted with 0-3 R^(b);    -   alternatively, two R⁷s form a 5- to 7-membered carbocyclic or        heterocyclic ring comprising: carbon atoms and 0-3 ring        heteroatoms selected from O, N, NR^(7b), and S(O)_(p), wherein        said carbocyclic or heterocyclic ring is substituted with 0-3        R^(7c);    -   R^(7b) is, independently at each occurrence, H, C₁₋₄ alkyl,        (C₁₋₄ alkyl)C(O)—, phenyl-C(O)—, benzyl-C(O)—, benzyl-S(O)₂—,        (C₁₋₄ alkyl)NHC(O)—, (C₁₋₄ alkyl)₂NC(O)—, phenyl-NHC(O)—,        benzyl-NHC(O)—, (C₁₋₄ alkyl)-S(O)₂—, phenyl-S(O)₂—, phenyl        substituted with 0-3 R^(b), or benzyl substituted with 0-3        R^(b);    -   R^(7c) is, independently at each occurrence, H, F, Cl, Br, I,        OCF₃, CF₃, OR^(c), SR^(c), CN, NO₂, —NR¹²R¹³, —C(O)R^(c),        —C(O)OR^(c), —C(O)NR¹²R¹³, —NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³,        —S(O)R^(d), —S(O)₂R^(d), C₁₋₄ alkyl, phenyl substituted with 0-3        R^(b), or benzyl substituted with 0-3 R^(b);

R¹¹ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with1-5 fluorine, —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³, C₁₋₈ alkyl substituted with0-2 R^(a), C₂₋₈ alkenyl substituted with 0-2 R^(a), C₂₋₈ alkynylsubstituted with 0-2 R^(a), (C₁₋₆ alkyl)C(O)—, (C₃₋₆ cycloalkyl)C₁₋₃alkyl-C(O)—, (C₃₋₆ cycloalkyl)C(O)—, phenyl-C(O)—, benzyl-C(O)—, (C₁₋₆alkyl)NHC(O)—, (C₁₋₆ alkyl)₂NC(O)—, phenyl-NHC(O)—, benzyl-NHC(O)—,(phenyl)(C₁₋₆ alkyl)NC(O)—, (benzyl)(C₁₋₆ alkyl)NC(O)—, (C₁₋₆alkyl)-S(O)₂—, phenyl-S(O)₂—, benzyl-S(O)₂—, —(CR^(f)R^(f))_(r)—C₃₋₁₀carbocycle, or —(CR^(f)R^(f))_(r)-5- to 10-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, NR^(f), O,and S(O)_(p); wherein said phenyl, benzyl, carbocycle, and heterocycleare substituted with 0-3 R^(b);

R¹² is, independently at each occurrence, H, C₁₋₆ alkyl substituted with1-5 fluorine, —CH₂O(C₁₋₄ alkyl), —(CR^(f)R^(f))_(r)C(O)NR^(f)R^(f), C₁₋₆alkyl, (C₁₋₆ alkyl)C(O)—, (C₁₋₄ alkyl)OC(O)—, (C₆₋₁₀ aryl)-CH₂—OC(O)—,(C₆₋₁₀ aryl)-CH₂—C(O)—, (C₁₋₄ alkyl)-C(O)O—(C₁₋₄ alkyl)-OC(O)—, (C₆₋₁₀aryl)-C(O)O—(C₁₋₄ alkyl)-OC(O)—, (C₁₋₆ alkyl)-NHC(O)—, (C₆₋₁₀aryl)-NHC(O)—, (5- to 10-membered heteroaryl)-NHC(O)—, (5- to10-membered heteroaryl)-CH₂—OC(O)—, (5- to 10-memberedheteroaryl)-C(O)—, (C₆₋₁₀ aryl)-(C₀₋₄ alkyl)-C(O)—, (C₁₋₆ alkyl)-S(O)₂—,(C₆₋₁₀ aryl)-S(O)₂—, (5- to 10-membered heteroaryl)-S(O)₂—, or (C₆₋₁₀aryl)-(C₁₋₄ alkyl)-S(O)₂—, —(CR^(f)R^(f))_(n)—(C₆₋₁₀ aryl),—(CR^(f)R^(f))_(n)-5- to 10-membered heterocycle; wherein said alkyl,phenyl and aryl are substituted with 0-2 R^(g); said 5- to 10-memberedheteroaryl is substituted with with 0-2 R^(g)and comprises: carbon atomsand 1-4 heteroatoms selected from N, NR^(f), O, and S(O)_(p); said 5- to10-membered heterocycle is substituted with with 0-2 R^(g)and comprises:carbon atoms and 1-4 heteroatoms selected from N, NR^(f), O, andS(O)_(p);

-   -   R¹³ is, independently at each occurrence, H, C₁₋₆ alkyl, or        —(CH₂)_(n)-phenyl;    -   alternatively, R¹² and R¹³, when attached to the same nitrogen,        combine to form a 5- to 10-membered heterocyclic ring        comprising: carbon atoms and 1-2 additional heteroatoms selected        from N, NR^(f), O, and S(O)_(p);    -   R¹⁴ is, independently at each occurrence, H, C₁₋₆ alkyl        substituted with 0-2 R^(14a), C₂₋₆ alkenyl substituted with 0-2        R^(14a), C₂₋₆ alkynyl substituted with 0-2 R^(14a),        —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(g), or        —(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon        atoms and 1-4 heteroatoms selected from N, NR^(f), O, and        S(O)_(p), wherein said heterocycle is substituted with 0-3        R^(g);    -   R^(14a) is, independently at each occurrence, H, C₁₋₄ alkyl,        OR^(f), Cl, F, Br, I, ═O, CF₃, CN, NO₂, NR¹²R¹³, —C(O)R^(f),        —C(O)OR^(f), —C(O)NR¹²R¹³, or —S(O)_(p)R^(f);

R¹⁵ is H, C₁₋₆ alkyl substituted with 0-2 R^(a), C₂₋₆ alkenylsubstituted with 0-2 R^(a), C₂₋₆ alkynyl substituted with 0-2 R^(a),(C₁₋₆ alkyl)C(O)—, (C₃₋₆ cycloalkyl)C₁₋₃ alkyl-C(O)—, (C₃₋₆cycloalkyl)C(O)—, phenyl-C(O)—, benzyl-C(O)—, benzyl-S(O)₂—, (C₁₋₆alkyl)NHC(O)—, (C₁₋₆ alkyl)₂NC(O)—, phenyl-NHC(O)—, benzyl-NHC(O)—,(phenyl)(C₁₋₆ alkyl)NC(O)—, (benzyl)(C₁₋₆ alkyl)NC(O)—, (C₁₋₆alkyl)-S(O)₂—, phenyl-S(O)₂—, —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(b), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, NR^(f), O, andS(O)_(p), wherein said heterocycle is substituted with 0-3 R^(b);

-   -   R¹⁶ is, independently at each occurrence, H, F, Cl, Br, I, OCF₃,        CF₃, —(CH₂)_(r)—OR^(c), SR^(c), CN, NO₂, —(CH₂)_(r)—NR¹²R¹³,        —(CH₂)_(r)—C(O)R^(c), —(CH₂)_(r)—CO₂R^(c),        —(CH₂)_(r)—C(O)NR¹²R¹³, —(CH₂)_(r)—OC(O)NR¹²R¹³,        —(CH₂)_(r)—NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³,        —NR¹⁴S(O)_(p)NR¹²R¹³, —NR¹⁴SO₂CF₃, —NR¹⁴SO₂R^(d), —S(O)₂CF₃,        —S(O)R^(d), —S(O)₂R^(d), C₁₋₆ alkyl substituted with 0-2 R^(a),        C₂₋₆ alkenyl substituted with 0-2 R^(a), C₂₋₆ alkynyl        substituted with 0-2 R^(a), —(CH₂)_(r)—C₃₋₁₀ carbocycle        substituted with 0-5 R^(b), or —(CH₂)_(r)-5- to 10-membered        heterocycle comprising: carbon atoms and 1-4 heteroatoms        selected from N, NR^(f), O, and S(O)_(p), wherein said        heterocycle is substituted with 0-5 R^(b);    -   R¹⁷ is, independently at each occurrence, H, OH, C₁₋₆ alkyl, or        —(CH₂)_(n)-phenyl;    -   R^(a) is, independently at each occurrence, H, F, OCF₃, CF₃,        —(CR^(f)R^(f))_(r)OR_(c), —(CR^(f)R^(f))_(r)SR^(c), CN,        —(CR^(f)R^(f))_(r)NR¹²R¹³, —(CR^(f)R^(f))_(r)C(O)R^(c),        —(CR^(f)R^(f))_(r)C(O)OR^(c), —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³,        —(CR^(f)R^(f))_(r)NR¹⁴C(O)R^(d),        —(CR^(f)R^(f))_(r)S(O)_(p)NR¹²R¹³, —(CR^(f)R^(f))_(r)S(O)R^(d),        —(CR^(f)R^(f))_(r)S(O)₂R^(d), C₁₋₄ alkyl substituted with 1-5        fluorine, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3        R^(e), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:        carbon atoms and 1-4 heteroatoms selected from N, NR^(f), O, and        S(O)_(p), wherein said heterocycle is substituted with 0-3        R^(e);    -   R^(b) is, independently at each occurrence, H, ═O, F, Cl, Br, I,        —(CH₂)_(r)—OR^(c), SR^(c), CN, NO₂, CF₃, OCF₃,        —(CR^(f)R^(f))_(r)NR¹²R¹³, —C(O)R^(c), —(CH₂)_(r)—C(O)OR^(c),        —(CH₂)_(r)—C(O)NR¹²R¹³, —NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³,        —S(O)R^(d), —S(O)₂R^(d), C₁₋₄ haloalkyl, C₁₋₄ haloalkyloxy-,        C₁₋₆ alkyl substituted with 0-2 R^(a), C₂₋₆ alkenyl substituted        with 0-2 R^(a), C₂₋₆ akynyl substituted with 0-2 R^(a),        —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(e), or        —(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon        atoms and 1-4 heteroatoms selected from N, NR^(f), O, and        S(O)_(p), wherein said heterocycle is substituted with 0-3        R^(e);

R^(c) is, independently at each occurrence, H, —OP(O)(OEt)₂, C₁₋₈ alkylsubstituted with 0-2 R^(e), C₂₋₈ alkenyl substituted with 0-2 R^(e),C₂₋₈ alkynyl substituted with 0-2 R^(e), —(CR^(f)R^(f))_(r)—C₃₋₈cycloalkyl substituted with 0-2 R^(e), —(CR^(f)R^(f))_(r)—C₆₋₁₀ arylsubstituted with 0-2 R^(e), or —(CR^(f)R^(f))_(r)-5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, NR^(f), O, and S(O)_(p), wherein said heterocycle is substituted with0-2 R^(e);

R^(d) is, independently at each occurrence, CF₃, OH, C₁₋₄ alkoxy, C₁₋₆alkyl, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-2 R^(e), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, NR^(f), O, and S(O)_(p), wherein saidheterocycle is substituted with 0-2 R^(e);

-   -   R^(e) is, independently at each occurrence, H, ═O,        —(CH₂)_(r)—OR^(f), F, Cl, Br, I, CN, NO₂, —(CH₂)_(r)—NR¹²R¹³,        —C(O)R^(f), —(CH₂)_(r)—C(O)OR^(f), —NR¹⁴C(O)R^(f),        —(CH₂)_(r)—C(O)NR¹²R¹³, —SO₂NR¹²R¹³, —NR¹⁴SO₂NR¹²R¹³,        —NR¹⁴SO₂—C₁₋₄ alkyl —NR¹⁴SO₂CF₃, —NR¹⁴SO₂-phenyl, —S(O)₂CF₃,        —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, —(CF₂)_(r)CF₃, Si(C₁₋₄        alkyl)₃, C₁₋₈ alkyl substituted with 0-2 R^(g), C₂₋₈ alkenyl        substituted with 0-2 R^(g), C₂₋₈ alkynyl substituted with 0-2        R^(g), —(CH₂)_(r)—C₃₋₈ cycloalkyl substituted with 0-2 R^(g),        —(CH₂)_(r)—C₆₋₁₀ aryl substituted with 0-2 R^(g), or        —(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon        atoms and 1-4 heteroatoms selected from N, NR^(f), O, and        S(O)_(p), wherein said heterocycle is substituted with 0-2        R^(g);    -   alternatively, two R^(e) groups, together with the atoms to        which they are attached, form a 5- to 7-membered carbocyclic or        heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms        selected from N, NR^(f), O, and S(O)_(p), 0-1 carbonyl and 0-3        double bonds, wherein said carbocyclic or heterocyclic ring is        substituted with 0-3 R^(g);    -   R^(f) is, independently at each occurrence, H, F, C₁₋₆ alkyl, or        —(CH₂)_(n)-phenyl;    -   R^(g) is, independently at each occurrence, H, ═O, OR^(f), F,        Cl, Br, I, CN, NO₂, —NR^(f)R^(f), —C(O)R^(f), —C(O)OR^(f),        —NR^(f)C(O)R^(f), —C(O)NR^(f)R^(f), —SO₂NR^(f)R^(f),        —NR^(f)SO₂NR^(f)R^(f), —NR^(f)SO₂—C₁₋₄ alkyl, —NR^(f)SO₂CF₃,        —NR^(f)SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl,        —S(O)_(p)-phenyl, —(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, or        C₂₋₆ alkynyl;    -   R^(h) is, independently at each occurrence, C₁₋₆ alkyl        substituted with 0-2 R^(g), or —(CH₂)_(n)-phenyl substituted        with 0-2 R^(g), or —(CH₂)_(n)-5- to 10-membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from N,        NR^(f), O, and S(O)_(p), wherein said heterocycle is substituted        with 0-2 R^(g);    -   R^(i) is, independently at each occurrence, H, C₁₋₆ alkyl        substituted with 0-2 R^(g), —(CH₂)_(n)-phenyl substituted with        0-2 R^(g), or —(CH₂)_(n)-5- to 10-membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from N,        NR^(f), O, and S(O)_(p), wherein said heterocycle is substituted        with 0-2 R^(g);    -   n, at each occurrence, is selected from 0, 1, 2, 3, and 4;    -   p, at each occurrence, is selected from 0, 1, and 2;    -   r, at each occurrence, is selected from 0, 1, 2, 3, and 4;    -   s, at each occurrence, is selected from 0, 1, 2, 3, 4, 5, and 6;        and    -   t, at each occurrence, is selected from 1, 2, 3, and 4;    -   provided that when Y is S, R⁵ is Ph or 6-NO₂-pyridyl, ring A is        other than 2-imidazolinyl or 6-NO₂-pyridyl.

In another embodiment, the present invention includes, inter alia, amethod for treating a thromboembolic disorder, comprising: administeringto a patient in need thereof a therapeutically effective amount of acompound of Formula (Ia):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate,or prodrug thereof, wherein:

-   -   ring A is a 5- to 6-membered heteroaryl comprising: carbon atoms        and 1-4 ring heteroatoms selected from N, NR¹¹, S(O)_(p), and O,        wherein said heteroaryl is substituted with 0-4 R¹;    -   ring B is phenyl substituted with 0-4 R⁷, pyridyl substituted        with 0-3 R⁷, or thienyl substituted with 0-2 R⁷;    -   X is NH or NMe;    -   Y is O or S;    -   R¹ is, independently at each occurrence, F, Cl, Br, I, CF₃,        —CF₂CF₃, OCF₃, —OCF₂CF₂H, —OCF₂CF₃, SiMe₃,        —(CR^(f)R^(f))_(r)—OR^(c), SR^(c), CN, NO₂,        —(CR^(f)R^(f))_(r)—NR¹²R¹³, —(CR^(f)R^(f))_(r)—C(O)R^(c),        —(CR^(f)R^(f))_(r)—CO₂R^(c), —(CR^(f)R^(f))_(r)—C(O)NR¹²R¹³,        —C(O)NR¹⁴(CR^(f)R^(f))_(t)N¹²R¹³,        —(CR^(f)R^(f))_(r)—OC(O)NR¹²R¹³,        —(CR^(f)R^(f))_(r)—NR¹⁴C(O)NR¹²R¹³,        —(CR^(f)R^(f))_(r)—NR¹⁴C(O)R^(d),        —(CR^(f)R^(f))_(r)—NR¹⁴C(O)OR^(h),        —NR¹⁴(CR^(f)R^(f))_(n)C(O)R^(d), —NR¹⁴CO(CR^(f)R^(f))_(n)OR^(c),        —(CH₂)_(r)—CR¹³(═NOR^(c)), —(CH₂)_(r)—C(NH₂)(═NOR^(c)),        —S(O)_(p)NR¹²R¹³, —(CR^(f)R^(f))_(r)—NR¹⁴S(O)_(p)NR¹²R¹³,        —NR¹⁴SO₂CF₃, —NR¹⁴S(O)_(p)R^(d), —S(O)₂CF₃, —S(O)R^(d),        —S(O)₂R^(d), —OP(O)(OEt)₂, —O(CH₂)₂OP(O)(OEt)₂,        4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl, C₁₋₈ alkyl substituted        with 0-2 R^(a), C₂₋₈ alkenyl substituted with 0-2 R^(a), C₂₋₈        alkynyl substituted with 0-2 R^(a), —(CR^(f)R^(f))_(r)—C₃₋₁₃        carbocycle substituted with 0-5 R^(b), or —(CR^(f)R^(f))_(r)-5-        to 10-membered heterocycle comprising: carbon atoms and 1-4        heteroatoms selected from N, NR¹¹, O, and S(O)_(p), wherein said        heterocycle is substituted with 0-5 R^(b);    -   alternatively, two R¹s are combined with the carbon atoms to        which they attached, form a 5- to 7-membered carbocycle or        heterocycle comprising: carbon atoms and 0-3 additional        heteroatoms selected from N, NR¹¹, O, and S(O)_(p), 0-2        carbonyls, and 0-2 double bond, wherein said carbocycle or        heterocycle is substituted with 0-4 R^(b);    -   R⁵ is a —(CR^(f)R^(f))_(n)—C₃₋₁₀ carbocycle substituted with 0-4        R^(5a), or a —(CR^(f)R^(f))_(n)-5- to 10-membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from N,        NR¹¹, O, and S(O)_(p), wherein said heterocycle is substituted        with 0-4 R^(5a); provided that R⁵ is other than unsubstituted        phenyl;    -   R^(5a) is, independently at each occurrence, F, Cl, Br, I,        —(CR^(i)R^(i))_(r)—OR^(c), SR^(c), CN, NO₂, CF₃, —CF₂CF₃, OCF₃,        —OCF₂CF₂H, —OCF₂CF₃, —NR¹²R³, —C(O)R^(c), —C(O)OR^(c),        —C(O)NR¹²R¹³, —NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³, —S(O)R^(d),        —S(O)₂R^(d), —Si(Me)₃, Si(C₁₋₄ alkyl)₃, C₁₋₄ haloalkyl, C₁₋₄        haloalkyloxy-, C₁₋₄ alkyloxy-, C₁₋₄ alkylthio-, C₁₋₄        alkyl-C(O)—, C₁₋₄ alkyl-O—C(O)—, C₁₋₄ alkyl-C(O)NH—, C₁₋₈ alkyl        substituted with 0-2 R^(a), C₂₋₈ alkenyl substituted with 0-2        R^(a), C₂₋₈ alkynyl substituted with 0-2 R^(a),        —(CR^(f)R^(f))_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(e),        or —(CR^(f)R^(f))_(r)-5- to 10-membered heterocycle comprising:        carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and        S(O)_(p), wherein said heterocycle is substituted with 0-3        R^(e);    -   alternatively, two R^(5a) groups, together with the atoms to        which they are attached, form a 5- to 7-membered carbocyclic or        heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms        selected from N, NR¹¹, O, and S(O)_(p), 0-1 carbonyl and 0-3        double bonds, wherein said carbocyclic or heterocyclic ring is        substituted with 0-3 R^(e);    -   R⁷ is, independently at each occurrence, H, F, Cl, Br, I, OCF₃,        CF₃, OR^(c), SR^(c), CN, NO₂, —NR¹²R¹³, —C(O)R^(c), —C(O)OR^(c),        —C(O)NR¹²R¹³, —NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³, —S(O)R^(d),        —S(O)₂R^(d), C₁₋₈ alkyl substituted with 0-2 R^(a), C₂₋₈ alkenyl        substituted with 0-2 R^(a), C₂₋₈ alkynyl substituted with 0-2        R^(a), —(CR^(f)R^(f))_(r)—C₃₋₁₀ carbocycle substituted with 0-3        R^(b), or —(CR^(f)R^(f))_(r)-5- to 10-membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from N,        NR^(7b), O, and S(O)_(p), wherein said heterocycle is        substituted with 0-3 R^(b);    -   alternatively, two R⁷s form a 5- to 7-membered carbocyclic or        heterocyclic ring comprising: carbon atoms and 0-3 ring        heteroatoms selected from O, N, NR^(7b), and S(O)_(p), wherein        said carbocyclic or heterocyclic ring is substituted with 0-3        R^(7c);    -   R^(7b) is, independently at each occurrence, H, C₁₋₄ alkyl,        (C₁₋₄ alkyl)C(O)—, phenyl-C(O)—, benzyl-C(O)—, benzyl-S(O)₂—,        (C₁₋₄ alkyl)NHC(O)—, (C₁₋₄ alkyl)₂NC(O)—, phenyl-NHC(O)—,        benzyl-NHC(O)—, (C₁₋₄ alkyl)-S(O)₂—, phenyl-S(O)₂—, phenyl        substituted with 0-3 R^(b), or benzyl substituted with 0-3        R^(b);

R^(7c) is, independently at each occurrence, H, F, Cl, Br, I, OCF₃, CF₃,OR^(c), SR^(c), CN, NO₂, —NR¹²R¹³, —C(O)R^(c), —C(O)OR^(c),—C(O)NR¹²R¹³, —NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³, —S(O)R^(d), —S(O)₂R^(d),C₁₋₄ alkyl, phenyl substituted with 0-3 R^(b), or benzyl substitutedwith 0-3 R^(b);

-   -   R¹¹ is, independently at each occurrence, H, C₁₋₆ alkyl        substituted with 1-5 fluorine, —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³,        C₁₋₈ alkyl substituted with 0-2 R^(a), C₂₋₈ alkenyl substituted        with 0-2 R^(a), C₂₋₈ alkynyl substituted with 0-2 R^(a), (C₁₋₆        alkyl)C(O)—, (C₃₋₆ cycloalkyl)C₁₋₃ alkyl-C(O)—, (C₃₋₆        cycloalkyl)C(O)—, phenyl-C(O)—, benzyl-C(O)—, (C₁₋₆        alkyl)NHC(O)—, (C₁₋₆ alkyl)₂NC(O)—, phenyl-NHC(O)—,        benzyl-NHC(O)—, (phenyl)(C₁₋₆ alkyl)NC(O)—, (benzyl)(C₁₋₆        alkyl)NC(O)—, (C₁₋₆ alkyl)-S(O)₂—, phenyl-S(O)₂—, benzyl-S(O)₂—,        —(CR^(f)R^(f))_(r)—C₃₋₁₀ carbocycle, or —(CR^(f)R^(f))_(r)-5- to        10-membered heterocycle comprising: carbon atoms and 1-4        heteroatoms selected from N, NR^(f), O, and S(O)_(p); wherein        said phenyl, benzyl, carbocycle, and heterocycle are substituted        with 0-3 R^(b);    -   R¹² is, independently at each occurrence, H, C₁₋₆ alkyl        substituted with 1-5 fluorine, —CH₂O(C₁₋₄ alkyl),        —(CR^(f)R^(f))_(r)C(O)NR^(f)R^(f), C₁₋₆ alkyl, (C₁₋₆        alkyl)C(O)—, (C₁₋₄ alkyl)OC(O)—, (C₆₋₁₀ aryl)-CH₂—OC(O)—, (C₆₋₁₀        aryl)-CH₂—C(O)—, (C₁₋₄ alkyl)-C(O)O—(C₁₋₄ alkyl)-OC(O)—, (C₆₋₁₀        aryl)-C(O)O—(C₁₋₄ alkyl)-OC(O)—, (C₁₋₆ alkyl)-NHC(O)—, (C₆₋₁₀        aryl)-NHC(O)—, (5- to 10-membered heteroaryl)-NHC(O)—, (5- to        10-membered heteroaryl)-CH₂—OC(O)—, (5- to 10-membered        heteroaryl)-C(O)—, (C₆₋₁₀ aryl)-(C₀₋₄ alkyl)-C(O)—, (C₁₋₆        alkyl)-S(O)₂—, (C₆₋₁₀ aryl)-S(O)₂—, (5- to 10-membered        heteroaryl)-S(O)₂—, or (C₆₋₁₀ aryl)-(C₁₋₄ alkyl)-S(O)₂—,        —(CR^(f)R^(f))_(n)—(C₆₋₁₀ aryl), —(CR^(f)R^(f))_(n)-5- to        10-membered heterocycle; wherein said alkyl, phenyl and aryl are        substituted with 0-2 R^(g); said 5- to 10-membered heteroaryl is        substituted with with 0-2 R^(g)and comprises: carbon atoms and        1-4 heteroatoms selected from N, NR^(f), O, and S(O)_(p); said        5- to 10-membered heterocycle is substituted with with 0-2 R^(g)        and comprises: carbon atoms and 1-4 heteroatoms selected from N,        NR^(f), O, and S(O)_(p);    -   R¹³ is, independently at each occurrence, H, C₁₋₆ alkyl, or        —(CH₂)_(n)-phenyl;    -   alternatively, R¹² and R¹³, when attached to the same nitrogen,        combine to form a 5- to 10-membered heterocyclic ring        comprising: carbon atoms and 1-2 additional heteroatoms selected        from N, NR^(f), O, and S(O)_(p);    -   R¹⁴ is, independently at each occurrence, H, C₁₋₆ alkyl        substituted with 0-2 R¹⁴, C₂₋₆ alkenyl substituted with 0-2        R^(14a), C₂₋₆ alkynyl substituted with 0-2 R^(14a),        —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(g), or        —(CH₂)_(r)-5 to 10-membered heterocycle comprising: carbon atoms        and 1-4 heteroatoms selected from N, NR^(f), O, and S(O)_(p),        wherein said heterocycle is substituted with 0-3 R^(g);    -   R^(14a) is, independently at each occurrence, H, C₁₋₄ alkyl,        OR^(f), Cl, F, Br, I, ═O, CF₃, CN, NO₂, NR¹²R¹³, —C(O)R^(f),        —C(O)OR^(f), —C(O)NR¹²R¹³, or —S(O)_(p)R^(f);    -   R^(a) is, independently at each occurrence, H, F, OCF₃, CF₃,        —(CR^(f)R^(f))_(r)OR^(c), —(CR^(f)R^(f))_(r)SR^(c), CN,        —(CR^(f)R^(f))_(r)NR¹²R¹³, —(CR^(f)R^(f))_(r)C(O)R^(c),        —(CR^(f)R^(f))_(r)C(O)OR^(c), —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³,        —(CR^(f)R^(f))_(r)NR¹⁴C(O)R^(d),        —(CR^(f)R^(f))_(r)S(O)_(p)NR¹²R¹³, —(CR^(f)R^(f))_(r)S(O)R^(d),        —(CR^(f)R^(f))_(r)S(O)₂R^(d), C₁₋₄ alkyl substituted with 1-5        fluorine, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3        R^(e), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:        carbon atoms and 1-4 heteroatoms selected from N, NR^(f), O, and        S(O)_(p), wherein said heterocycle is substituted with 0-3        R^(e);    -   R^(b) is, independently at each occurrence, H, ═O, F, Cl, Br, I,        —(CH₂)_(r)—OR^(c), SR^(c), CN, NO₂, CF₃, OCF₃,        —(CR^(f)R^(f))_(r)NR¹²R¹³, —C(O)R^(c), —(CH₂)_(r)—C(O)OR^(c),        —(CH₂)_(r)—C(O)NR¹²R¹³, —NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³,        —S(O)R^(d), —S(O)₂R^(d), C₁₋₄ haloalkyl, C₁₋₄ haloalkyloxy-,        C₁₋₆ alkyl substituted with 0-2 R^(a), C₂₋₆ alkenyl substituted        with 0-2 R^(a), C₂₋₆ alkynyl substituted with 0-2 R^(a),        —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(e), or        —(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon        atoms and 1-4 heteroatoms selected from N, NR^(f), O, and        S(O)_(p), wherein said heterocycle is substituted with 0-3        R^(e);    -   R^(c) is, independently at each occurrence, H, —OP(O)(OEt)₂,        C₁₋₈ alkyl substituted with 0-2 R^(e), C₂₋₈ alkenyl substituted        with 0-2 R^(e), C₂₋₈ akynyl substituted with 0-2 R^(e),        —(CR^(f)R^(f))_(r)—C₃₋₈ cycloalkyl substituted with 0-2 R^(e),        —(CR^(f)R^(f))_(r)—C₆₋₁₀ aryl substituted with 0-2 R^(e), or        —(CR^(f)R^(f))_(r)-5- to 10-membered heterocycle comprising:        carbon atoms and 1-4 heteroatoms selected from N, NR^(f), O, and        S(O)_(p), wherein said heterocycle is substituted with 0-2        R^(e);    -   R^(d) is, independently at each occurrence, CF₃, OH, C₁₋₄        alkoxy, C₁₋₆ alkyl, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with        0-2 R^(e), or —(CH₂)_(r)-5- to 10-membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from N,        NR^(f), O, and S(O)_(p), wherein said heterocycle is substituted        with 0-2 R^(e);    -   R^(e) is, independently at each occurrence, H, ═O,        —(CH₂)_(r)—OR^(f), F, Cl, Br, I, CN, NO₂, —(CH₂)_(r)—NR¹²R¹³,        —C(O)R^(f), —(CH₂)_(r)—C(O)OR^(f), —NR¹⁴C(O)R^(f),        —(CH₂)_(r)—C(O)NR¹²R¹³, —SO₂NR¹²R¹³, —NR¹⁴SO₂NR¹²R¹³,        —NR¹⁴SO₂—C₁₋₄ alkyl, —NR¹⁴SO₂CF₃, —NR¹⁴SO₂-phenyl, —S(O)₂CF₃,        —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, —(CF₂)_(r)CF₃, Si(C₁₋₄        alkyl)₃, C₁₋₈ alkyl substituted with 0-2 R^(g), C₂₋₈ alkenyl        substituted with 0-2 R^(g), C₂₋₈ alkynyl substituted with 0-2        R^(g), —(CH₂)_(r)—C₃₋₈ cycloalkyl substituted with 0-2 R^(g),        —(CH₂)_(r)—C₆₋₁₀ aryl substituted with 0-2 R^(g), or        —(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon        atoms and 1-4 heteroatoms selected from N, NR^(f), O, and        S(O)_(p), wherein said heterocycle is substituted with 0-2        R^(g);    -   alternatively, two R^(e) groups, together with the atoms to        which they are attached, form a 5- to 7-membered carbocyclic or        heterocyclic ring comprising: carbon atoms and 0-2 heteroatoms        selected from N, NR^(f), O, and S(O)_(p), 0-1 carbonyl and 0-3        double bonds, wherein said carbocyclic or heterocyclic ring is        substituted with 0-3 R^(g);    -   R^(f) is, independently at each occurrence, H, F, C₁₋₆ alkyl, or        —(CH₂)_(n)-phenyl;    -   R^(g) is, independently at each occurrence, H, ═O, OR^(f), F,        Cl, Br, I, CN, NO₂, —NR^(f)R^(f), —C(O)R^(f), —C(O)OR^(f),        —NR^(f)C(O)R^(f), —C(O)NR^(f)R^(f), —SO₂NR^(f)R^(f),        —NR^(f)SO₂NR^(f)R^(f), —NR^(f)SO₂—C₁₋₄ alkyl, —NR^(f)SO₂CF₃,        —NR^(f)SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl,        —S(O)_(p)-phenyl, —(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, or        C₂₋₆ alkynyl;    -   R^(h) is, independently at each occurrence, C₁₋₆ alkyl        substituted with 0-2 R^(g), or —(CH₂)_(n)-phenyl substituted        with 0-2 R^(g), or —(CH₂)_(n)-5- to 10-membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from N,        NR^(f), O, and S(O)_(p), wherein said heterocycle is substituted        with 0-2 R^(g);    -   R^(i) is, independently at each occurrence, H, C₁₋₆ alkyl        substituted with 0-2 R^(g), —(CH₂)_(n)-phenyl substituted with        0-2 R^(g), or —(CH₂)_(n)-5- to 10-membered heterocycle        comprising: carbon atoms and 1-4 heteroatoms selected from N,        NR^(f), O, and S(O)_(p), wherein said heterocycle is substituted        with 0-2 R^(g);    -   n, at each occurrence, is selected from 0, 1, 2, 3, and 4;    -   p, at each occurrence, is selected from 0, 1, and 2; and    -   r, at each occurrence, is selected from 0, 1, 2, 3, and 4;

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, tautomer, pharmaceuticallyacceptable salt, solvate, or prodrug thereof.

In another embodiment, the present invention provides a novel processfor making a compound of the present invention or a stereoisomer,tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof.

In another embodiment, the present invention provides a novelintermediate for making a compound of the present invention or astereoisomer, tautomer, pharmaceutically acceptable salt, solvate orprodrug thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising additional therapeutic agent(s) selected frompotassium channel openers, potassium channel blockers, calcium channelblockers, sodium hydrogen exchanger inhibitors, antiarrhythmic agents,antiatherosclerotic agents, anticoagulants, antithrombotic agents,prothrombolytic agents, fibrinogen antagonists, diuretics,antihypertensive agents, ATPase inhibitors, mineralocorticoid receptorantagonists, phospodiesterase inhibitors, antidiabetic agents,anti-inflammatory agents, antioxidants, angiogenesis modulators,antiosteoporosis agents, hormone replacement therapies, hormone receptormodulators, oral contraceptives, antiobesity agents, antidepressants,antianxiety agents, antipsychotic agents, antiproliferative agents,antitumor agents, antiulcer and gastroesophageal reflux disease agents,growth hormone agents and/or growth hormone secretagogues, thyroidmimetics, anti-infective agents, antiviral agents, antibacterial agents,antifungal agents, cholesterol/lipid lowering agents and lipid profiletherapies, and agents that mimic ischemic preconditioning and/ormyocardial stunning, or a combination thereof

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising additional therapeutic agent(s) are selected froman anti-arrhythmic agent, an anti-hypertensive agent, an anti-coagulantagent, an anti-platelet agent, a thrombin inhibiting agent, athrombolytic agent, a fibrinolytic agent, a calcium channel blocker, apotassium channel blocker, a cholesterol/lipid lowering agent, or acombination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising additional therapeutic agent(s) selected fromwarfarin, unfractionated heparin, low molecular weight heparin,synthetic pentasaccharide, hirudin, argatroban, aspirin, ibuprofen,naproxen, sulindac, indomethacin, mefenamate, dipyridamol, droxicam,diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel,tirofiban, eptifibatide, abciximab, melagatran, ximelagatran,disulfatohirudin, tissue plasminogen activator, modified tissueplasminogen activator, anistreplase, urokinase, and streptokinase, or acombination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising additional therapeutic agent(s) anantihypertensive agent selected from ACE inhibitors, AT-1 receptorantagonists, ET receptor antagonists, dual ET/AII receptor antagonists,and vasopepsidase inhibitors, or an antithrombotic agent selected froman antiplatelet agent selected from GPIIb/IIIa blockers, P2Y₁ and P2Y₁₂antagonists, thromboxane receptor antagonists, and aspirin, or acombination thereof.

In another embodiment, the present invention provides a method formodulation of platelet reactivity comprising administering to a patientin need of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a a stereoisomer,tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, the present invention provides a method fortreating thromboembolic disorders comprising: administering to a patientin need of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or a a stereoisomer,tautomer, pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another embodiment, the thromboembolic disorder is selected from thegroup consisting of arterial cardiovascular thromboembolic disorders,venous cardiovascular thromboembolic disorders, arterial cerebrovascularthromboembolic disorders, venous cerebrovascular thromboembolicdisorders, and thromboembolic disorders in the chambers of the heart.

In another embodiment, the thromboembolic disorder is selected from thegroup consisting of unstable angina, an acute coronary syndrome, atrialfibrillation, first myocardial infarction, recurrent myocardialinfarction, ischemic sudden death, transient ischemic attack, stroke,atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis.

In another embodiment, the present invention provides a novel method oftreating a patient in need of thromboembolic disorder treatment,comprising: administering a compound of the present invention or astereoisomer, tautomer, pharmaceutically acceptable salt, solvate, orprodrug thereof in an amount effective to treat a thromboembolicdisorder.

In another embodiment, the present invention provides a method fortreating a thromboembolic disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a firstand additional therapeutic agent(s), wherein the first therapeutic agentis a compound of present invention or a pharmaceutically acceptable saltthereof and the additional therapeutic agent(s) are selected frompotassium channel openers, potassium channel blockers, calcium channelblockers, sodium hydrogen exchanger inhibitors, antiarrhythmic agents,antiatherosclerotic agents, anticoagulants, antithrombotic agents,prothrombolytic agents, fibrinogen antagonists, diuretics,antihypertensive agents, ATPase inhibitors, mineralocorticoid receptorantagonists, phospodiesterase inhibitors, antidiabetic agents,anti-inflammatory agents, antioxidants, angiogenesis modulators,antiosteoporosis agents, hormone replacement therapies, hormone receptormodulators, oral contraceptives, antiobesity agents, antidepressants,antianxiety agents, antipsychotic agents, antiproliferative agents,antitumor agents, antiulcer and gastroesophageal reflux disease agents,growth hormone agents and/or growth hormone secretagogues, thyroidmimetics, anti-infective agents, antiviral agents, antibacterial agents,antifungal agents, cholesterol/lipid lowering agents and lipid profiletherapies, and agents that mimic ischemic preconditioning and/ormyocardial stunning, or a combination thereof.

In another embodiment, the present invention provides a method fortreating a thromboembolic disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a firstand additional therapeutic agent(s), wherein the first therapeutic agentis a compound of present invention or a pharmaceutically acceptable saltthereof and the additional therapeutic agent(s) are selected from ananti-arrhythmic agent, an anti-hypertensive agent, an anti-coagulantagent, an anti-platelet agent, a thrombin inhibiting agent, athrombolytic agent, a fibrinolytic agent, a calcium channel blocker, apotassium channel blocker, a cholesterol/lipid lowering agent, or acombination thereof.

In another embodiment, the present invention provides a method fortreating a thromboembolic disorder, wherein the additional therapeuticagent(s) are selected from warfarin, unfractionated heparin, lowmolecular weight heparin, synthetic pentasaccharide, hirudin,argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin,mefenamate, dipyridamol, droxicam, diclofenac, sulfinpyrazone,piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab,melagatran, ximelagatran, disulfatohirudin, tissue plasminogenactivator, modified tissue plasminogen activator, anistreplase,urokinase, and streptokinase, a combination thereof.

In another embodiment, the present invention provides a method fortreating a thromboembolic disorder, wherein the additional therapeuticagent(s) are selected from an antihypertensive agent selected from ACEinhibitors, AT-1 receptor antagonists, ET receptor antagonists, dualET/AII receptor antagonists, and vasopepsidase inhibitors, or anantithrombotic agent selected from an antiplatelet agent selected fromGPIIb/IIIa blockers, P2Y₁ and P2Y₁₂ antagonists, thromboxane receptorantagonists, and aspirin, a combination thereof.

In another embodiment, the present invention provides a method fortreating a thromboembolic disorder, wherein the additional therapeuticagent(s) are an anti-platelet agent or a combination thereof.

In another embodiment, the present invention provides a method fortreating a thromboembolic disorder, wherein the additional therapeuticagent(s) are the anti-platelet agent(s) clopidogrel and/or aspirin.

In another embodiment, the present invention provides a novel method,comprising: administering a compound of the present invention in anamount effective to treat a thromboembolic disorder.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention also provides the use of acompound of the present invention for the manufacture of a medicamentfor the treatment of a thromboembolic disorder.

In another embodiment, the present invention provides a novel article ofmanufacture, comprising: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention; and (c) a package insert stating that thepharmaceutical composition can be used for the treatment of athromboembolic disorder.

In another preferred embodiment, the present invention provides a novelarticle of manufacture, further comprising: (d) a second container;wherein components (a) and (b) are located within the second containerand component (c) is located within or outside of the second container.

In another embodiment, the present invention provides a novel article ofmanufacture, comprising: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention; and (c) a package insert stating that thepharmaceutical composition can be used in combination with a secondtherapeutic agent to treat a thromboembolic disorder.

In another preferred embodiment, the present invention provides a novelarticle of manufacture, further comprising: (d) a second container;wherein components (a) and (b) are located within the second containerand component (c) is located within or outside of the second container.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional more preferredembodiments. It is also to be understood that each individual element ofthe preferred embodiments is its own independent preferred embodiment.Furthermore, any element of an embodiment is meant to be combined withany and all other elements from any embodiment to describe an additionalembodiment.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Geometric isomers of double bonds such as olefins and C═N double bondscan also be present in the compounds described herein, and all suchstable isomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention. All tautomers of shown or described compounds are alsoconsidered to be part of the present invention.

The following are definitions of terms used in this specification. Theinitial definition provided for a group or term herein applies to thatgroup or term throughout the present specification, individually or aspart of another group, unless otherwise indicated.

Preferably, the molecular weight of compounds of the present inventionis less than about 500, 550, 600, 650, 700, 750, or 800 grams per mole.Preferably, the molecular weight is less than about 800 grams per mole.More preferably, the molecular weight is less than about 750 grams permole. Even more preferably, the molecular weight is less than about 700grams per mole.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbon atom of the carbonyl group or one carbon atom of thedouble bond be part of (i.e., within) the ring. Ring double bonds, asused herein, are double bonds that are formed between two adjacent ringatoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these can be converted to N-oxides by treatmentwith an oxidizing agent (e.g., MCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, all shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative. In cases wherein there are quartemary carbonatoms on compounds of the present invention, these can be replaced bysilicone atoms, provided they do not form Si—N or Si—O bond.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R¹, then said group mayoptionally be substituted with up to three R¹ groups and R¹ at eachoccurrence is selected independently from the definition of R¹. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “alkyl” or “alkylene” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁₋₁₀ alkyl”(or alkylene), is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈,C₉, and C₁₀ alkyl groups. Additionally, for example, “C₁₋₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, butare not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl,2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither a straight or branched configuration having the specified numberof carbon atoms and one or more unsaturated carbon-carbon bonds whichmay occur in any stable point along the chain. For example, “C₂₋₆alkenyl” (or alkenylene), is intended to include C₂, C₃, C₄, C₅, and C₆alkenyl groups. Examples of alkenyl include, but are not limited to,ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3,pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither a straight or branched configuration and one or morecarbon-carbon triple bonds which may occur in any stable point along thechain. For example, “C₂₋₆ alkynyl” (or alkynylene), is intended toinclude C₂, C₃, C₄, C₅, and C₆ alkynyl groups; such as ethynyl,propynyl, butynyl, pentynyl, hexynyl and the like.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. C₃₋₇ cycloalkyl is intended to includeC₃, C₄, C₅, C₆, and C₇ cycloalkyl groups. Example cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbomyl, and the like.

“Alkoxy” or “alkyloxy” represents an alkyl group as defined above withthe indicated number of carbon atoms attached through an oxygen bridge.For example, “C₁₋₆ alkoxy” (or alkyloxy), is intended to include C₁, C₂,C₃, C₄, C₅, and C₆ alkoxy groups. Examples of alkoxy include, but arenot limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy,s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Similarly, “alkylthio” or“thioalkoxy” represents an alkyl group as defined above with theindicated number of carbon atoms attached through a sulphur bridge; forexample methyl-S—, ethyl-S—, and the like.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate, and thelike.

“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen. Examples of haloalkylinclude, but are not limited to, trifluoromethyl, trichloromethyl,pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl,heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl alsoinclude “fluoroalkyl” which is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more fluorineatoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluorothoxy, and the like. Similarly,“haloalkylthio” or “thiohaloalkoxy” represents a haloalkyl group asdefined above with the indicated number of carbon atoms attached througha sulphur bridge; for example trifluoromethyl-S—, pentafluoroethyl-S—,and the like.

As used herein, “carbocycle” is intended to mean any stable 3, 4, 5, 6,or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or13-membered bicyclic or tricyclic, any of which may be saturated,partially unsaturated, or aromatic. Examples of such carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,or tetrahydronaphthyl (tetralin). Preferred carbocycles, unlessotherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, phenyl, naphthyl, and indanyl. When the term “carbocycle” isused, it is intended to include “aryl”.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem which contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5 or 6 membered carbon ring which is saturated,partially unsaturated, or unsaturated. The bicyclic carbocyclic groupmay be attached to its pendant group at any carbon atom which results ina stable structure. The bicyclic carbocyclic group described herein maybe substituted on any carbon if the resulting compound is stable.Examples of a bicyclic carbocyclic group are, but not limited to,naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.

As used herein, the term “aryl”, “C₆₋₁₀ aryl” or “aromatic residue”, isintended to mean an aromatic moiety containing, if specified, thespecified number of carbon atoms; for example phenyl or naphthyl. Unlessotherwise specified, “aryl”, “C₆₋₁₀ aryl” or “aromatic residue” may beunsubstituted or substituted with 0 to 3 groups selected from H, OH,OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, C(═O)CH₃,SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, and CO₂CH₃.

As used herein, the term “heterocycle” or “heterocyclic group” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, 10, 11, 12, 13, or 14-membered bicyclic heterocyclic ring whichis saturated, partially unsaturated or fully unsaturated, and whichconsists of carbon atoms and 1, 2, 3 or 4 heteroatoms independentlyselected from the group consisting of N, O and S; and including anybicyclic group in which any of the above-defined heterocyclic rings isfused to a benzene ring. The nitrogen and sulfur heteroatoms mayoptionally be oxidized to —NO—, —SO—, or —SO₂—. The heterocyclic ringmay be attached to its pendant group at any heteroatom or carbon atomwhich results in a stable structure. The heterocyclic rings describedherein may be substituted on carbon or on a nitrogen atom if theresulting compound is stable. If specifically noted, a nitrogen in theheterocycle may optionally be quatemized. It is preferred that when thetotal number of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

As used herein, the term “aromatic heterocyclic system” or “heteroaryl”is intended to mean monocyclic and polycyclic aromatic hydrocarbon thatinclude at least one heteroatom ring member such as sulfur, oxygen, ornitrogen. Preferred heteroaryl groups are stable 5, 6, or 7-memberedmonocyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromaticrings which consists of carbon atoms and 1, 2, 3, or 4 heteroatomsindependently selected from the group consisting of N, NH, O and S. Itis to be noted that total number of S and O atoms in the aromaticheterocycle is not more than 1. Heteroaryl groups include, withoutlimitation, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furanyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrryl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide,benzoxazolin-2-on-yl, indolinyl, benzodioxolanyl, benzodioxane, and thelike. Heteroaryl groups can be substituted or unsubstituted.

Examples of heterocycles include, but are not limited to,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, imidazolopyridinyl, 1H-indazolyl, indolenyl,indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl,oxazolidinylperimidinyl, oxindolyl, phenanthridinyl, phenanthrolinyl,phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl,phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl,4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl,pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, carbolinyl, tetrazolyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thiazolopyridinyl, thienyl,thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, and xanthenyl.

Preferred 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Preferred 5- to 6-membered heterocycles include, but are not limited to,pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5 or 6-membered monocyclic aromatic ring comprising a 5 memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5 or 6 membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5 membered heterocycle, a 6 membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinoline, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxaline, and 1,2,3,4-tetrahydro-quinazoline.

Bridged rings are also included in the definition of carbocycle orheterocycle. A bridged ring occurs when one or more atoms (i.e., C, O,N, or S) link two non-adjacent carbon or nitrogen atoms. Preferredbridges include, but are not limited to, one carbon atom, two carbonatoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogengroup. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Compounds of the present invention, and salts thereof, may exist intheir tautomeric form, in which hydrogen atoms are transposed to otherparts of the molecules and the chemical bonds between the atoms of themolecules are consequently rearranged. It should be understood that alltautomeric forms, insofar as they may exist, are included within theinvention. Additionally, inventive compounds may have trans and cisisomers and may contain one or more chiral centers, therefore existingin enantiomeric and diastereomeric forms. The invention includes allsuch isomers, as well as mixtures of cis and trans isomers, mixtures ofdiastereomers and racemic mixtures of enantiomers (optical isomers).When no specific mention is made of the configuration (cis, trans or Ror S) of a compound (or of an asymmetric carbon), then any one of theisomers or a mixture of more than one isomer is intended. The processesfor preparation can use racemates, enantiomers, or diastereomers asstarting materials. When enantiomeric or diastereomeric products areprepared, they can be separated by conventional methods, for example, bychromatographic or fractional crystallization. The inventive compoundsmay be in the free or hydrate form.

Isotopically labeled compounds of the present invention, i.e., whereinone or more of the atoms described are replaced by an isotope of thatatom (e.g., C replaced by ¹³C or by ¹⁴C; and isotopes of hydrogeninclude tritium and deuterium), are also provided herein. Such compoundshave a variety of potential uses, e.g., as standards and reagents indetermining the ability of a potential pharmaceutical to bind to targetproteins or receptors, or for imaging compounds of this invention boundto biological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

-   -   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985),        and Methods in Enzymology, Vol. 42, at pp. 309-396, edited by K.        Widder, et. al. (Academic Press, 1985);    -   b) A Textbook of Drug Design and Development, edited by        Krosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and        Application of Prodrugs,” by H. Bundgaard, at pp. 113-191        (1991);    -   c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, p.        1-38(1992);    -   d) H. Bundgaard, et al., Journal of Phannaceutical Sciences,        Vol. 77, p. 285 (1988); and    -   e) N. Kakeya, et. al., Chem Phar Bull., Vol. 32, p. 692 (1984).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters which serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C₁₋₆alkanoyloxy-C₁₋₆alkyl, e.g. acetoxymethyl, pivaloyloxymethyl orpropionyloxymethyl, C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl, e.g.methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl,phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl andother well known physiologically hydrolyzable esters used, for example,in the penicillin and cephalosporin arts. Such esters may be prepared byconventional techniques known in the art.

It should further be understood that solvates (e.g., hydrates) of thecompounds of the present invention are also with the scope of thepresent invention. Methods of solvation are generally known in the art.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

Therapeutically effective amount“is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit P2Y₁. “Therapeutically effectiveamount” is also intended to include an amount of the combination ofcompounds claimed that is effective to inhibit P2Y₁. The combination ofcompounds is preferably a synergistic combination. Synergy, asdescribed, for example, by Chou and Talalay, Adv. Enzyme Regul. 1984,22, 27-55, occurs when the effect (in this case, inhibition of P2Y₁) ofthe compounds when administered in combination is greater than theadditive effect of the compounds when administered alone as a singleagent. In general, a synergistic effect is most clearly demonstrated atsub-optimal concentrations of the compounds. Synergy can be in terms oflower cytotoxicity, increased antithrombotic effect, or some otherbeneficial effect of the combination compared with the individualcomponents.

The present invention further includes compositions comprising one ormore compounds of the present invention and a pharmaceuticallyacceptable carrier.

A “pharmaceutically acceptable carrier” refers to media generallyaccepted in the art for the delivery of biologically active agents toanimals, in particular, mammals. Pharmaceutically acceptable carriersare formulated according to a number of factors well within the purviewof those of ordinary skill in the art. These include, withoutlimitation: the type and nature of the active agent being formulated;the subject to which the agent-containing composition is to beadministered; the intended route of administration of the composition;and, the therapeutic indication being targeted. Pharmaceuticallyacceptable carriers include both aqueous and non-aqueous liquid media,as well as a variety of solid and semi-solid dosage forms. Such carrierscan include a number of different ingredients and additives in additionto the active agent, such additional ingredients being included in theformulation for a variety of reasons, e.g., stabilization of the activeagent, binders, etc., well known to those of ordinary skill in the art.Descriptions of suitable pharmaceutically acceptable carriers, andfactors involved in their selection, are found in a variety of readilyavailable sources such as, for example, Remington's PharmaceuticalSciences, 17th ed., 1985, which is incorporated herein by reference inits entirety.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “M” for molar, “mmol” for millimoleor millimoles, “min” for minute or minutes, “h” for hour or hours, “rt”for room temperature, “atm” for atmosphere, “psi” for pounds per squareinch, “conc.” for concentrate, “sat” or “sat'd ” for saturated, “MW” formolecular weight, “mp” for melting point, “MS” or “Mass Spec” for massspectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR”for high resolution, “LC-MS” for liquid chromatography massspectrometry, “HPLC” for high pressure liquid chromatography, “RP HPLC”for reverse phase HPLC, “TLC” for thin layer chromatography, “NMR” fornuclear magnetic resonance spectroscopy, “¹H” for proton, “δ” for delta,“s” for singlet, “d” for doublet, “t” for triplet, “q” for quartet, “m”for multiplet, “br” for broad, “Hz” for hertz, “tlc” for thin layerchromatography, and “α”, “β”, “R”, “S”, “E”, and “Z” are stereochemicaldesignations familiar to one skilled in the art.

-   -   Me methyl    -   Et ethyl    -   MeOH methanol    -   EtOH ethanol    -   i-PrOH isopropanol    -   Ph phenyl    -   Bn benzyl    -   t-Bu tertiary butyl    -   AcOH acetic acid    -   EtOAc ethyl acetate    -   2MeS-ADP 2 methylthio adenosine diphosphate    -   cDNA complimentary DNA    -   DBAD Di-tert-butylazodicarboxylate    -   DEAD Diethylazodicarboxyalte    -   DIPEA N,N,-diisopropylethylamine    -   DMEM Dulbecco's modified Eagle media    -   DMF dimethyl formamide    -   DMSO dimethyl sulfoxide    -   DCE 1,2 dichloroethane    -   DCM dichloromethane    -   DCC dicyclohexylcarbodiimide    -   DIC or DIPCDI diisopropylcarbodiimide    -   DIEA diethylpropyl amine    -   EDC (or EDC.HCl) or EDCI (or EDCI.HCl) or EDAC        3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or        1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)    -   EDTA ethylenediaminetetraacetic acid    -   FBS Fetal Bovine Serum    -   HEPES 4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid    -   HOBt 1-Hydroxybenzotriaole hydrate    -   iPr₂NEt N,N,-diisopropylethylamine    -   LDA Lithium diisopropylamide    -   LiHMDS Lithium bis(trimethylsilyl amide)    -   MCPBA meta-chloroperbenzoic acid    -   D-PBS Dulbecco's Phosphate Buffered Saline    -   Pd/C palladium on carbon    -   PCy₃ Tricyclohexyl phosphine    -   SCX Strong Cation Exchanger    -   TBTU O-Benzotriazol-1-yl-N,N.N′,N′-tetramethyluronium        tetrafluoroborate    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   TRIS tris (hydroxymethyl) aminomethane

Solution ratios express a volume relationship, unless stated otherwise.NMR chemical shifts (δ) are reported in parts per million. Flashchromatography was carried out on silica gel according to Still's method(Still, W. C. et al. J. Org. Chem. 1978, 43, 2923). Alternatively, flashchromatography was carried out on an ISCO CombiFlash™ System Sq16× usingprepacked SiO₂ cartridges eluted with gradients of hexanes and ethylacetate.

SYNTHESIS

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention.

A particularly useful compendium of synthetic methods which may beapplicable to the preparation of compounds of the present invention maybe found in Larock, R. C. Comprehensive Organic Transformations, VCH:New York, 1989. Preferred methods include, but are not limited to, thosedescribed below. All references cited herein are hereby incorporated intheir entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents that are compatible withthe reaction conditions will be readily apparent to one skilled in theart and alternate methods must then be used.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing many alternatives to one skilled in theart is Greene and Wuts (Protective Groups In Organic Synthesis, Wileyand Sons, 1991). All references cited herein are hereby incorporated intheir entirety herein by reference.

Scheme 1 describes the preparation of compounds of the invention fromfunctionalized intermediates of formula 1.1 wherein X, for example, is anucleophilic nitrogen or oxygen species. Coupling of intermediates offormula 1.1 with intermediates of formula 1.2 wherein G, for example, isa halide or tosylate can be accomplished thermally by methods known toone skilled in the art of organic synthesis at temperatures between −78°C. and 250° C. in a variety of solvents such as, for example,tetrahydrofuran, ethanol, dichloroethane, dichloromethane, toluene,dimethylformamide or dioxane provides compounds of the invention offormula 1.3. Alternately, coupling of intermediates of formula 1.1 withintermediates of formula 1.2 wherein G, for example, is a halide,tosylate, boronic acid, boronate ester, or trialkylstanane can beaccomplished using metal catalyzed couplings known to one skilled in theart of organic synthesis or described herein at temperatures between−78° C. and 250° C. in a variety of solvents such as, for example,tetrahydrofuran, ethanol, dichloroethane, dichloromethane, toluene,dimethylformamide or dioxane provides compounds of the invention offormula 1.3. A variety of examples of such metal catalyzed couplings areprovided the following articles and book: Muci, A. R.; Buchwald, S. L.Top. Curr. Chem. 2002, 219, 131. and Hartwig, J. F. In Modern AminationMethods; Ricci, A., Ed., Wiley-VCH: Weinheim, Germany, 2000. The metalcatalyst is usually palladium or nickel complexed with ligands such as adiphosphine or a ferrocene.

In similar fashion as described above, intermediates of formula 1.4 andformula 1.5 can be coupled to provide compounds of the invention offormula 1.3.

Intermediates of formula 1.1, 1.2, 1.4 and 1.5 are commerciallyavailable or can readily be prepared from commercially availablematerials by methods known to one skilled in the art of organicsynthesis or can be prepared from commercially available materialsthrough schemes and examples provided herein.

Scheme 2 describes the preparation of compounds of the invention fromfunctionalized intermediates of formula 2.1 wherein Y, for example, is anucleophilic nitrogen, sulfur or oxygen species. Coupling ofintermediates of formula 2.1 with intermediates of formula 2.2 whereinG, for example, is a halide or tosylate can be accomplished thermally bymethods known to one skilled in the art of organic synthesis attemperatures between −78° C. and 250° C. in a variety of solvents suchas, for example, tetrahydrofuran, ethanol, dichloroethane,dichloromethane, toluene, dimethylformamide or dioxane providescompounds of the invention of formula 2.3. Alternately, coupling ofintermediates of formula 2.1 with intermediates of formula 2.2 whereinG, for example, is a halide, tosylate, boronic acid, boronate ester, ortrialkylstanane can be accomplished using metal catalyzed couplingsknown to one skilled in the art of organic synthesis or described hereinat temperatures between −78° C. and 250° C. in a variety of solventssuch as, for example, tetrahydrofuran, ethanol, dichloroethane,dichloromethane, toluene, dimethylformamide or dioxane providescompounds of the invention of formula 2.3. A variety of examples of suchmetal catalyzed couplings are provided the following articles and book:Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. andHartwig, J. F. In Modern Amination Methods; Ricci, A., Ed., Wiley-VCH:Weinheim, Germany, 2000. The metal catalyst is usually palladium ornickel complexed with ligands such as a diphosphine or a ferrocene.

In similar fashion as described above, intermediates of formula 2.4 andformula 2.5 can be coupled to provide compounds of the invention offormula 2.3. Intermediates of formula 2.1, 2.2, 2.4 and 2.5 arecommercially available or can readily be prepared from commerciallyavailable materials by methods known to one skilled in the art oforganic synthesis or can be prepared from commercially availablematerials through schemes and examples provided herein.

Scheme 3 describes the preparation of compounds of the invention fromflinctionalized intermediates of formula 3.1 wherein Z is a nitrogen orsulfur. Treatment of intermediate 3.1 with reagents such as, forexample, α-haloketones or α-haloaldehydes, or equivalent reagents, in asolvent such as, for example, ethanol with or without a base such as,for example, 2,6-lutudine or NaOAc at temperatures between 0° C. to 110°C. provides compounds of the invention of formula 3.3. (Similarchemistry for Z=sulfur described in: Udapudi, V. T. et al. IndianJournal of Chemistry, Section B: Organic Chemistry Including MedicinalChemistry 1986, 25B(12), 1269-72. Singh, S. P.; et. al. Indian Journalof Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry1985, 24B(1), 119-23.)

Scheme 4 describes the preparation of compounds of the invention fromfunctionalized intermediates of formula 4.1. Treatment of intermediate4.1 with reagents such as, for example, α-azidoketones orα-azidoaldehydes, or equivalent reagent, and triphenylphosphine, orequivalent reagent, in a solvents such as, for example, toluene or DMFat temperatures between 0° C. to 150° C. provides compounds of theinvention of formula 4.3. α-Azidoketones and α-azidoaldehydes can beprepared by methods known to one skilled in the art of syntheticchemistry from the corresponding commercially available α-haloketones orα-haloaldehydes, or equivalent reagents.

Scheme 5 describes the preparation of compounds of the invention fromfunctionalized intermediates of formula 5.1. Treatment of intermediate5.1 with amidines of formula 5.2 in a solvent such as, for example,dimethylformamide at temperatures between 70° C. to 120° C. provideintermediates formula 5.3. Treatment of intermediates of formula 5.3with DEAD (M. Furukawa et al., Synthesis, 1990, 1020-1023), or anequivalent reagent, in a solvent such as, for example, ethanol oracetonitrile at temperatures between 0° C. to 70° C. provide compoundsof the invention of formula 5.4. Amidines 5.2 are commercially availableor can be prepared by methods known to one skilled in the art ofsynthetic chemistry (such as described in M. Anbazhagan, D. W. Boykin,C. E. Stephens, Synthesis, 2003, 2467-2469.)

Scheme 6 describes the preparation of compounds of the invention fromfunctionalized intermediates of formula 6.1. Treatment of thioisocyanateintermediate 6.1 with acylhydrazides of formula 6.2 in a solvent suchas, for example, dichloromethane at temperatures between 0° C. to 50° C.provide intermediates formula 6.3. Treatment of intermediates of formula6.3 with an acid such as, for example, neat sulfuric acid or anequivalent reagent, at temperatures between 0° C. to 20° C. providecompounds of the invention of formula 6.4. Acylhydrazides of formula 6.2are commercially available or can be prepared from carboxylic acids,acyl chlorides or equivalent reagents by methods known to one skilled inthe art of synthetic chemistry.

Alternately compounds of the invention of formula 6.4 can be prepared bytreatment of intermediate 6.1 with tert-butyl carbazate 6.6, or anequivalent reagent, in a solvent such as, for example, dichloromethaneat temperature between 0° C. to 50° C. Subsequent removal of thetert-butoxycarbonyl with an acid such as, for example, TFA in a solventsuch as, for example, dichloromethane provides intermediates of formula6.7. Treatment of intermediates of formula 6.7 with an acyl chloride, orsimilar suitably activated acylating reagent, in a solvent such as, forexample, tetrahydrofuran at temperatures between 0° C. to 50° C.provides intermediates of the formula 6.3. Treatment of intermediates offormula 6.3 with an acid such as, for example, neat sulfuric acid or anequivalent reagent such as trifloroacetic acid, at temperatures between0° C. to 20° C. provide compounds of the invention of formula 6.4.

Scheme 7 describes the preparation of compounds of the invention fromfunctionalized intermediates of formula 7.1. Treatment of isocyanateintermediate 7.1 with acylhydrazides of formula 7.2 in a solvent suchas, for example, tetrahydrofiran at temperatures between 20° C. to 65°C. provide intermediates formula 7.3. Treatment of intermediates offormula 7.3 with triphenylphosphine, or an equivalent reagent, in asolvent such as, for example, hexachloroethane, with a base such as, forexample, triethylamine, at temperatures between 0° C. to 50° C. providecompounds of the invention of formula 7.4. Acylhydrazides of formula 7.2are commercially available or can be prepared from carboxylic acids,acyl chlorides or equivalent reagents by methods known to one skilled inthe art of synthetic chemistry.

Scheme 8 describes the preparation of compounds of the invention fromfunctionalized intermediates of formula 8.1. Treatment of intermediatesof formula 8.1 with acyl isothiocyanates of formula 8.2 in a solventsuch as, for example, tetrahydrofuran at temperatures between −78° C. to70° C. provides intermediates of formula 8.3. Treatment of intermediatesof formula 8.4 with a base such as, for example, sodium hydride followedby treatment with an alkylating agent such as, for example, methyliodidein a solvent such as, for example, THF at temperatures between −78° C.to 70° C. provides intermediates of formula 8.4. Treatment ofintermediates of formula 8.4 with hydroxylamine in a solvent such as,for example, THF at temperatures between −78° C. to 20° C. providescompounds of the invention of formula 8.5 (T. G. M. Dhar et al. Bioorg.Med. Chem. Lett. 2002, 12, 3125). Acylisothiocyanates of formula 8.2 arecommercially available or can be prepared from carboxylic acids, acylchlorides or equivalent reagents by methods known to one skilled in theart of synthetic chemistry.

Scheme 9 describes the preparation of compounds of the invention fromfunctionalized intermediates of formula 9.1. Treatment ketones oraldehydes of formula 9.2 with a base such as, for example, sodiumhydride in a solvent such as, for example, dimethylformamide attemperatures between −78° C. to 20° C. with subsequent addition ofisothiocyanate intermediates of formula 9.1 provide intermediates offormula 9.3. Treatment of intermediates of formula 9.3 with a base suchas, for example, sodium hydride followed by treatment with an alkylatingagent such as, for example, methyliodide in a solvent such as, forexample, THF at temperatures between −78° C. to 70° C. providesintermediates of formula 9.4. Treatment of intermediates of formula 9.4with hydroxylamine in a solvent such as, for example, dimethylformamideat temperatures between −78° C. to 70° C. provides compounds of theinvention of formula 9.5. Ketones and aldehydes of formula 9.2 arecommercially available or can be prepared from carboxylic acids, acylchlorides, alcohols or equivalent reagents by methods known to oneskilled in the art of synthetic chemistry.

Scheme 10 describes the preparation of additional compounds of theinvention from functionalized intermediates of formula 10.1(intermediate 9.3 as described previously). Treatment of intermediatesof formula 10.1 with hydrazine, or an equivalent reagent, in thepresence of an acid such as, for example, acetic acid in a solvent suchas, for example, ethanol, at temperatures between 20° C. to 70° C.provides compounds of the invention of formula 10.2. Treatment of 10.2with a base such as, for example, LDA or NaH followed by addition of analkylating reagent in a solvent such as, for example, tetrahydrofuran,dioxane or dimethyformamide provide compounds of the invention offormula 10.3 and 10.4.

Alternately treatment of intermediate 10.1 with reagents such as, forexample, alkyl, aryl or heteroaryl substituted hydrazines in thepresence of an acid such as, for example, acetic acid in a solvent suchas, for example, ethanol provides compounds of the invention of formula10.3.

Examples of R or R′ side-chains in Schemes 3 to 10 above are given inScheme 10A below. Form a masked aldehyde or ketone precursor, theconversion to the amines requires either a reductive amnination or a SN2displacement on an activated chloride:

Scheme 11 outlines a prepration of the key isothiocyanate intermediate11.2. Anilines 11.1 (prepared according to Schemes 5-6), can be treatedwith a thiophosgene equivalent in an organic solvent such asdichloromethane, dichloroethane or toluene, to produce the correspondingisothiocyanate. Thiophosgene equivalents include thiocarbonic acidO,O-dipyridin-2-yl ester1,1′-thiocarbonyldi-2,2′-pyridone, carbondisulfide, thiocarbonyl-diimidazole, and thiophosgene.

Scheme 12 outlines one possible preparation of amino derivatives 12.4,by aromatic nucleophilic substitution followed by reduction. Nitroarylderivatives or nitroheteroaryl derivatives 12.1, substituted in theortho position with a halogen (such as chlorine, fluorine or bromine),are commercially available or can readily be prepared by one skilled inthe art of organic synthesis. They can be reacted with nucleophiles suchas substituted alcohols, subtituted amines, or substituted thiols toprovide the corresponding ether, amine or thioether respectively.Typically, a nucleophile and a halonitro derivative are reacted in anorganic solvent such as THF, DMF, toluene, dioxane or n-butanol, inpresence of a base such as potassium carbonate, cesium carbonate,triethylamine, or DIEA. The temperature of the reaction is usuallybetween room temperature and reflux. Occasionally, microwave irradiationcan be used to accelerate the rate of reaction. The diaryl ethers arepreferably synthesized by reacting an ortho chloro-nitroaryl derivativewith a substituted phenol and cesium cabonate at 80° C. in DMF. Thediaryl amines are preferably synthesized by reacting an orthochloro-nitroaryl derivative with a substituted aniline and triethylaminein butanol at 210° C. using microwave irradiation.

Following aromatic nucleophilic substitution, the resulting nitroderivative 12.3 can be reduced to the correponding aniline. Typicalreducing conditions include hydrogenation in the presence of a metalcatalyst such as palladium or platinum. Reduction of 12.3 or analogs mayalso be accomplished by treatment with reducing agents such as SnCl₂, orzinc powder with amonium chloride. The nascent amine 12.4 can beconverted to a halide 12.5 by treatment of 12.4 with a reagent such as,for example, sodium nitrite in the presence of an acid such as, forexample, HCl in a solvent such as, for example, water at temperaturesbetween 0° C. to 60° C. Treatment of the halide 12.5 with a reagent suchas, for example, n-BuLi in a solvent such as, for example, THF at atemperature between −78° C. to −43° C. followed by treatment with areagent such as, for example, triisopropyloxyborane leads to theformation of an intermediate aryl or heteroaryl boronic ester which canbe converted to the corresponding boronic acid 12.6 with a mild basicaqueous hydrolysis.

All of the following references are incorporated herein by reference.For additional preparations of starting materials and intermediates usedherein, see U.S. patent application publications US20050203146 andUS2005/0261244, and U.S. application Ser. No. 11/126915.

INTERMEDIATES Intermediate 1 2-(2-tert-Butylphenoxy)-3-amiinopyridine

Intermediate 1a. 2-(2-tert-Butylphenoxy)-3-nitropyridine: A solution of2-chloro-3-nitropyridine (21.1 g, 133 mmol) in DMF (100 mL) was treatedwith 2-tert-butylphenol (23.5 mL, 153 mmol) and cesium carbonate (130 g,398 mmol). The mixture was heated at 80° C. for 30 h. The reaction wascooled to rt and the mixture was poured into water (1 L) with stirring.The resulting yellow precipitate was filtered, washed with water, andrecrystallized from ethanol to afford Intermediate 1a (32.8 g, 90%yield) as beige crystals; HPLC purity: 92%, 3.66 min (Method A); ¹H NMR(400 MHz, CD₃OD) 5 ppm 1.34 (s, 9 H), 6.93 (m, 1 H), 7.22 (m, 3 H), 7.47(m, 1 H), 8.31 (dd, J=4.82, 1.75 Hz, 1 H), 8.46 (dd, J=7.89, 1.75 Hz, 1H).

Intermediate 1: Intermediate 1a (7.2 g, 27 mmol) was dissolved in a 1:1mixture of methanol and ethyl acetate (160 mL). Palladium on charcoal(10%, 360 mg, 0.33 mmol) was added and the mixture was stirred overnightunder hydrogen atmosphere (40 psi). The reaction mixture was filteredover Celite® and concentrated to afford Intermediate 1 (7.2 g, 100%yield) as a white powder; HPLC purity: 100%, 2.87 min (Method A);[M+H]⁺=243.3.

Intermediate 2 2-(3-Isopropylphenoxy)-3-aminopyridine

Intermediate 2a. 2-(3-Isopropylphenoxy)-3-nitropyridine: To a solutionof meta-isopropylphenol (214 mg, 1.57 mmol) in dry DMF (3 mL) was addedcesium carbonate (587 mg, 1.8 mmol) followed by 2-chloro-3-nitropyridine(237 mg, 1.5 mmol). The mixture was heated at 180° C. for 700 s in aPersonal Chemistry microwave. The mixture was diluted with water (3 mL)and extracted with ethyl acetate (2×4 mL). The combined organic layerswere washed with 5% aqueous LiCl solution (2×1.5 mL), saturated Na₂CO₃(2×1.5 mL), water (1×1.5 mL), and then dried over Na₂SO₄. The solventwas removed in vacuo to yield Intermediate 2a (338 mg, 87% yield) as adark brown oil; HPLC purity: 90%, 2.89 min (Method B).

Intermediate 2. Intermediate 2a: (338 mg, 1.3 mmol) was dissolved in 1:1methanol/ethyl acetate (5 mL) and a small spatula of 10% Pd/C was added.The mixture was hydrogenated at 40 psi for 3.5 h. The catalyst wasremoved by filtering through a pad of Celite®. Solvent removal affordedIntermediate 2 (267 mg, 90% yield) as a brown oil; HPLC purity: 81%,2.89 min (Method B); [M+H]⁺=229.52.

Intermediate 3 2-(2-tert-Butylphenoxy)-3-aminothiophene

Intermediate 3a. 2-(2-tert-butylphenoxy)-3-nitrothiophene: To a solutionof 2-chloro-3-nitrothiophene (1.13 g, 6.93 mmol) in NMP (10 ml) in apressure vessel was added 2-tert-butylphenol (1.04 g, 6.93 mmol) andK₂CO₃ (1.0 g, 10.1 mmol). The reaction was flushed with nitrogen, sealedand then heated to 105° C. for 48 h. The reaction was cooled to rt,diluted with EtOAc (˜150 mL) and washed twice with saturated aqueousNaCl (2×150 mL). The aqueous washes were then back extracted with EtOAc.The combined organics were dried over MgSO₄, filtered and concentrated.

Intermediate 3: The residue from Intermediate 3a was taken up in THF (50ml) in a pressure vessel to which was added Raney Ni in water (˜300 mg)and a stir bar. The reaction was degassed under mild vacuum and thenplaced under hydrogen gas (60-65 psi) and then stirred under hydrogenfor ˜3 h. The reaction vessel was then charged again with hydrogen gas(back to 60-65 psi) and the reaction was stirred overnight. The catalystwas removed by filtration through Celite®, taking care not to allow thecake to dry and the solid catalyst to ignite. The Celite® pad was washedwith THF until no UV activity was observed in the eluent. Purificationby flash chromatography (110 g ISCO silica cartridge, 0 to 15% EtOAc inhexanes over 40 min., hold at 15% EtOAc in hexanes for 10 min., 50ml/min) provided Intermediate 3 (2.0 g). (M+H)⁺=248.3.

Intermediate 4 2-(2-tert-Butylphenoxy)benzenamine

Intermediate 4a. 1-tert-butyl-2-(2-nitrophenoxy)benzene: A mixture of2-chloronitrobenzene (9.5 g, 60 mmol), 2-t-butyl phenol (9.04 g, 60.2mmol) and potassium carbonate (10.6 g) in DMF was heated at 130° C. for6 days. The reaction was cooled to rt and partitioned between diethylether (400 mL) and water (500 mL). The organic layer was separated andthe aqueous layer was extracted with ether (3×100 mL). The combinedorganic layers were dried over magnesium sulfate, filtered andevaporated to give Intermeidate 4a (20 g). (M+H)⁺=216.23.

Intermediate 4: To a solution of Intermediate 4a (˜20 g, crude) inMeOH/THF (1:1, 200 mL) was added 10% Pd/C (2 g). The mixture washydrogenated under 75 psi overnight. The mixture was filtered throughCelite® cake and the filtrate was evaporated to give the crude productas a black oil. Purification by flash chromatography (0-30%EtOAc/hexane) provided Intermediate 4 (11 g) as a brown solid.

Intermediates 5-9 listed in Table 1 were prepared following theprocedures described for Intermediate 1. TABLE 1 Intermediate Structure(M + H)⁺ 5

271 6

259 7

257 8

265 9

259

Intermediate3,3-spiro-(4-(1-neopentylpiperidine))-1,3-dihydroisobenzofuran-4-ol

Intermediate 10a. (2-iodo-3-(methoxymethoxy)phenyl)methanol:(3-(Methoxymethoxy)phenyl)methanol (Tetrahedron, 2003, 59, 3201-3217)(12 g, 71.4 mmol) in benzene (400 mL) was stirred at 0° C. Butyllithium(1.6 M in hexanes, 89.2 mL, 142.8 mmol) was added and the mixture waswarmed to rt and stirred for 2 h. Diiodoethane (20.12 g, 71.4 mmol) in50 mL of benzene was added and stirring was continued for a period of 2h. A saturated solution of ammonium chloride was added and the solutionwas extracted twice using ethyl acetate. The organic phases werecombined, dried using MgSO₄ and evaporated in vacuo. The crude materialwas purified using flash chromatography (15 to 40% ethylacetate/hexanes) to yield the desired material (5.74 g).

Intermediate 10b.4-(methoxymethoxy)-3,3-spiro-(4-(1-neopentylpiperidine))-1,3-dihydroisobenzofuran:(2-Iodo-3-(methoxymethoxy)phenyl)methanol (2 g, 6.8 mmol) was diluted inTHF (40 mL) at rt and isopropylmagnesiumbromide (9.6 mL, 2.12 M/Et₂O,20.4 mmol) was added. The reaction mixture was stirred for 2 h andcooled down to −78° C. 1-Pivaloylpiperidin-4-one (2.5 g, 13.6 mmol) wasadded and mixture was slowly warmed to rt and stirred for a period of 2h. Methanesulfonylchloride (1.6 mL, 20.4 mmol) was added and mixture wasrefluxed for a period of 2 h. The mixture was cooled down, a saturatedsolution of ammonium chloride was added, and mixture was extracted twiceusing ethylacetate. The organic phase was dried (MgSO₄) and evaporatedin vacuo. The crude product was diluted in THF (40 mL) and lithiumaluminum hydride (516 mg, 13.6 mmol) was added at rt and stirred for 18h. Sodium sulfate decahydrate was added and and mixture was stirred for2 h. The reaction mixture was filtered over celite and evaporated invacuo. The crude product was purified on preparative HPLC to give thedesired material (170 mg). (M+H)⁺=320.

Intermediate 10:4-(Methoxymethoxy)-3,3-spiro-(4-(1-neopentylpiperidine))-1,3-dihydroisobenzofuran(170 mg, 0.53 mmol) was diluted in CH₂Cl₂ (5 mL), cooled at −78° C.Iodotrimethylsilane (145 μL, 1.06 mmol) was added, the reaction mixturewas warmed to rt and stirred for a period of 2 h. A 1 M sodiumthiosulfate solution was added and organic phase was separated, driedusing MgSO₄, and evaporated in vacuo. The mixture was directly purifiedon preparative HPLC to give the desired material (39 mg). (M+H)⁺=276.

Intermediate 11 3-neopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ol

A mixture of 2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ol (see Demarinis etal. J. Med. Chem. 1984, 27, 918-921) (60 mg, 0.37 mmol),trimethylacetaldehyde (400 μL, 3.7 mmol), trimethyl orthoformate (390μL, 3.7 mmol) and glacial acetic acid (40 μL) in 1-methyl-2-pyrolidinone(2.5 mL) was stirred at rt for 2.5 h. Sodium triacetoxyborohydride (388mg, 1.8 mmol) was then added and the mixture was stirred at roomtemperature for 16 h. The mixture was then loaded on top of a silicagel-SCX (sulfonic acid) column and eluted first with methanol, then with2 M ammonia in methanol. The latter fraction was evaporated and theresulting 3-neopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ol was usedin the next step without further purification. (M+H)⁺=234.0.

EXAMPLES

The following Examples have been prepared, isolated and characterizedusing the methods disclosed herein. The following Examples demonstrate apartial scope of the invention and are not meant to be limiting of thescope of the invention.

Example 12-(2-tert-Butylphenoxy)-N-(5-phenyl-1,3,4-thiadiazol-2-yl)pyridin-3-amine

Example 1a 2-(2-tert-Butylphenoxy)-3-isothiocyanatopyridine

A mixture of 2-(2-tert-Butylphenoxy)-3-aminopyridine (Example 203b)(5.21 g, 21.5 mmol) and 1,1′-thiocarbonyldi-2(1H)-pyridone (5 g, 21.5mmol) in DCM (100 mL) was stirred at rt for 18 h. The mixture wasevaporated and the solid was dissolved in hexanes/DCM (50 mL, 9/1). Theresidual solid was removed by filtration and the solution was evaporatedto provide the title compound as a brown solid. (M+H)⁺=285.

Example 1b 4-(2-(2-tert-Butylphenoxy)pyridin-3-yl)thiosemicarbazide

A mixture of Example 1a (1 g, 3.51 mmol) and tert-butylcarbazate (465mg, 3.51 mmol) in DCM (10 mL) was stirred at rt for 2 h. Trifluoroaceticacid (2 mL) was added and mixture was stirred for 2 h. The solvent wasremoved and the residue was dissolved in EtOAc (15 mL), washed withsaturated sodium bicarbonate solution, dried (anh. MgSO₄), filtered andevaporated to give the title compound (1.32 g) as a brown solid.(M+H)⁺=317.

Example 1

A mixture of Example 1b (100 mg, 0.32 mmol), benzoyl chloride (45 mg,0.32 mmol) in DCM (2 mL) was stirred at rt for 18 h. Trifluoroaceticacid (2 mL) was then added and mixture was stirred for 6 h. The solventwas removed and residue was purified by preparative HPLC to give thetitle compound (6 mg, TFA salt) as a white powder. (M+H)⁺=403; ¹H NMR(400 MHz, DMSO d₆) δ ppm 1.30 (s, 9 H), 6.93 (dd, J=7.83, 1.26 Hz, 1 H),7.10-7.17 (m, 2 H), 7.23 (td, J=7.83, 1.77, 1 H), 7.41 (dd, J=8.08, 1.77Hz, 1 H),7.48-7.54 (m, 3 H), 7.77 (dd, J=4.80, 1.77 Hz, 1H), 7.84-7.88(m, 2 H), 8.84 (d, J=9.35 Hz, 1 H), 10.47 (s, 1 H).

Examples 2-55 listed in Table 2 were prepared following the proceduredescribed for Example 1. TABLE 2

Example R^(1c) (M + H)⁺ 1 Ph 403 2 4-CF₃-Ph 471 3 4-t-Bu-Ph 459 44-Me-Ph 417 5 neopentyl 397 6 4-OCF₃-Ph 487 7 4-F-Ph 421 8 4-Ph-Ph 479 93-Cl-Ph 438 10 3-OCF₃-Ph 487 11 naphth-2-yl 453 12 3-Me-Ph 417 132-Cl-Ph 438 14 cyclohexyl 409 15 pyridin-2-yl 404 16

461 17 4-CN-Ph 428 18 4-OMe-Ph 433 19 1-Me-pyrrol-2-yl 406 203,5-diCl-Ph 472 21 4-NMe₂-Ph 446 22 2,5-diMe-furan-3-yl 421 23 2-OMe-Ph433 24 4-(4-Bn-piperazin-1-yl)-Ph 577 25 4-NO₂-Ph 448 26 cyclopentyl 39527 thien-2-yl 409 28 3-NMe₂-Ph 446 29 3-(4-Bn-piperazin-1-yl)-Ph 577 301-Bn-piperidin-4-yl 500 31 1-Bn-piperidin-3-yl 500 32 —CH₂OBn 447 33phenethyl 431 34 1-Ph-cyclopropyl 443 35 t-Bu 383 36 4-F-Bn 435 37cyclobutyl 381 38 4-NMe₂-Bn 460 39 pyridin-4-yl 404 40

548 41 1-Bn-pyrrolidin-3-yl 486 42 pyridin-3-yl 404 43 —CH₂-thien-2-yl423 44 4-OMe-Bn 447 45 i-Pr 369 46 isoxazol-5-yl 394 47 4-CH₂NMe₂-Ph 46048 cyclopropyl 367 49 4-(imidazol-1-yl)-Ph 469 50 1-Bn-azetidin-3-yl 47251 3-CH₂NMe₂-Ph 460 52 1-(1-Bn-piperidin-4-yl)-piperidin-4-yl 583 53 H327 54 2-Ph-piperidin-4-yl 486 55 —CH₂O(CH₂)₂OMe 415 93 —CON(Me)Bn 47496 —C(Me)₂(CH₂)₂CO₂Me 455 97 —C(Me)₂(CH₂)₂CON(Me)Bn 544 98—C(Me)₂(CH₂)₂CO(4-Bn-piperazin-1-yl) 599 99 —C(Me)₂CH₂CON(Me)Bn 530 100—C(Me)₂(CH₂)₃N(Me)Bn 530 101 —C(Me)₂(CH₂)₃(4-Bn-piperazin-1-yl) 585 102—(CH₂)₃N(Me)(Bn) 488 103 —(CH₂)₃(1,2,3,4-tetrahydroisoquinolin-2-yl) 500104 —(CH₂)₃-isoindolin-2-yl 486 105 —(CH₂)₃(4-Bn-piperazin-1-yl) 543 1061-Bn-4-Me-piperidin-4-yl 460 107 1-(2-Cl-Bn)-4-Me-piperidin-4-yl 549 1081-(2,5-diF-Bn)-4-Me-piperidin-4-yl 550 1091-(2,4-diF-Bn)-4-Me-piperidin-4-yl 550 1101-(2,6-diCl-Bn)-4-Me-piperidin-4-yl 583 1111-(CH₂-thien-2-yl)-4-Me-piperidin-4-yl 520 1121-(CH₂-cyclohexyl)-4-Me-piperidin-4-yl 520 1131-(CH₂-naphth-1-yl)-4-Me-piperidin-4-yl 564 1141-(3-CN-Bn)-4-Me-piperidin-4-yl 539 115 1-(2-CN-Bn)-4-Me-piperidin-4-yl539 116 1-(4-CN-Bn)-4-Me-piperidin-4-yl 539 1171-(CH₂-thiazol-2-yl)-4-Me-piperidin-4-yl 521 1181-(CH₂-furan-3-yl)-4-Me-piperidin-4-yl 504 119

514 120 1-neohexyl-4-Me-piperidin-4-yl 508 121

514 122 1-Me-2-Ph-piperidin-4-yl 500 1231-(CH₂-pyridin-2-yl)-4-Me-piperidin-4-yl 515 1241-(CH₂-pyridin-3-yl)-4-Me-piperidin-4-yl 515 125

527.74

Example 562-(2-tert-Butylphenoxy)-N-(3-phenyl-1,2,4-thiadiazol-5-yl)pyridin-3-amine

A mixture of 2-(2-tert-butylphenoxy)-3-isothiocyanatopyridine (Example1a) (100 mg, 0.35 mmol), diisopropylethylamine (186 μL, 1.05 mmol) andbenzamidine hydrochloride (55 mg, 0.35 mmol) in DMF (2 mL) was stirredat rt for 18 h. Diethylazodicarboxylate (110 μL, 0.7 mmol) was added andmixture was stirred for 4 h. The reaction mixture was purified bypreparative HPLC to give the title compound (110 mg, TFA salt) as awhite solid. (M+H)⁺=403. ¹H NMR (400 MHz, DMSO d₆) δ ppm 1.31 (s, 9 H),6.94 (dd, J=7.83, 1.26 Hz, 1 H), 7.16 (dd, J=7.58, 1.26 Hz, 1H),7.20-7.27 (m, 2 H), 7.44 (dd, J=8.09, 1.77, 1H), 7.48-7.56 (m, 3 H),7.79 (dd, J=4.80, 1.51 Hz, 1H), 8.20 (dd, J=7.83, 1.52 Hz, 2 H), 9.04(dd, J=7.83, 1.52 Hz, 1 H), 10.93 (s, 1 H).

Examples 57-92 listed in Table 3 were prepared following the proceduredescribed for Example 56. TABLE 3

Example R^(1c) (M + H)⁺ 56 Ph 403 57 t-Bu 383 58 2,6-diCl-pyridin-4-yl473 59 3,5-diCl-Ph 472 60

461 61 —CH₂O(4-t-Bu-Ph) 489 62 2,6-diCl-Bn 486 63 3-F-Ph 421 64 3-CF₃-Ph471 65 CF₃ 395 66 i-Pr 369 67 3-Cl-4-F-Ph 456 68 —CH₂O(4-Cl-Ph) 468 694-Cl-Ph 437 70 cyclopropyl 367 71 3,5-diOMe-Ph 463 72 —CH₂OPh 433 73thien-2-yl 409 74 benzo[b]thien-3-yl 459 75 2-F-Ph 421 76 —CH₂O(2-Cl-Ph)468 77 furan-3-yl 393 78 4-CF₃-Ph 471 79 4-Me-Ph 417 80 3-NO₂-Ph 448 814-t-Bu-Ph 459 82 4-OMe-Ph 433 83 pyridin-4-yl 404 84 pyridin-3-yl 404 853,4-diOMe-Ph 463 86 Me 341 87 4-SO₂Me-Ph 481 88 pyridin-2-yl 404 89pyrazin-2-yl 405 92 —CH₂-1,2,4-triazol-1-yl 408 94 —CH₂N(Me)Bn 460 95—CH₂-piperidin-1-yl 424 126 1-Bn-piperidin-4-yl 500

Example 93N-Benzyl-5-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-N-methyl-1,3,4-thiadiazole-2-carboxamide

Example 93a5-(2-(2-Butylphenoxy)pyridin-3-ylamino)-1,3,4-thiadiazole-2-carboxylicacid

A mixture of 4-(2-(2-tert-butylphenoxy)pyridin-3-yl)thiosemicarbazide(Example 1b) (640 mg, 2.02 mmol) and ethyl chlorooxoacetate (226 μL,2.02 mmol) in DCM (10 mL) was stirred at rt for 18 h. The mixture wasevaporated and the solid was dissolved in sulfuric acid (8 mL) andstirred for 3 h. The reaction mixture was cooled to 0° C. and water (50mL) was added. The solid formed was isolated by filtration. (M+H)⁺=399.The resulting crude solid and lithium hydroxide hydrate (424 mg, 10.1mmol) were added to THF (10 mL) and water (10 mL) and stirred at rt for3 h. Saturated ammonium chloride was added and the solution wasextracted twice using ethyl acetate. The organic phase was dried(MgSO₄), filtered and evaporated to give Example 93a (120 mg) as a brownsolid. (M+H)⁺=327.

Example 93

A mixture of Example 93a (100 mg, 0.27 mmol), TBTU (87 mg, 0.41 mmol)and N-benzylmethylamine (104 μL, 0.81 mmol) in DMF (2 mL) was stirred atrt for 18 h. The reaction mixture was purified by preparative HPLC togive Example 93 (18 mg, TFA salt) as a white powder. (M+H)⁺=474; ¹H NMR(400 MHz, DMSO d₆) δ ppm 1.30 (s, 9 H), 2.94 (s, 1.5H), 3.41 (s, 1.5H),4.70 (s, 1H), 5.25 (s, 1H), 6.94 (td, J=7.83, 1.26 Hz, 1 H), 7.09-7.20(m, 2 H), 7.24 (td, J=7.32, 1.77, 1H), 7.27-7.46 (m, 6H), 7.76 (dd,J=6.07, 1.76 Hz, 1 H), 8.78 (ddd, J=8.09, 7.83, 1.27 Hz, 1H), 10.62 (d,J=4.30 Hz, 1 H).

Example 94N-(3-((Benzyl(methyl)amino)methyl)-1,2,4-thiadiazol-5-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

A mixture of N-benzylmethylamine (68 μL, 0.53 mmol),diisopropylethylamine (187 μL, 1.06 mmol) and chloroacetamidinehydrochloride (68 mg, 0.53 mmol) in DMF (5 mL) was stirred at rt for 18h. 2-(2-tert-butylphenoxy)-3-isothiocyanatopyridine (Example 1a) (150mg, 0.53 mmol) was then added and mixture was stirred for 3 h at 80° C.The reaction mixture was cooled to rt and diethylazodicarboxylate (168μL, 1.06 mmol) was added and mixture was stirred for 2 h. The reactionmixture was purified by preparative HPLC to give Example 94 (2 mg, 2TFAsalt) as a white. (M+H)⁺=460. ¹H NMR (400 MHz, DMSO d₆) δ ppm 1.30 (s, 9H), 2.26 (s, 3H), 3.64 (s, 2H), 3.67 (s, 2H), 6.92 (dd, J=7.83, 1.26 Hz,1 H), 7.12-7.39 (m, 9 H), 7.42 (dd, J=7.83, 1.52, 1H), 7.76 (dd, J=5.05,1.26, 1H), 8.89 (d, J=7.58 Hz, 1H), 10.82 (s, 1 H).

Example 95 listed in Table 3 were prepared following the proceduredescribed for Example 94.

Example 96 Methyl4-(5-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-1,3,4-thiadiazol-2-yl)-4-methylpentanoate

A mixture of 5-methoxy-2,2-dimethyl-5-oxopentanoic acid (500 mg, 2.87mmol), oxalyl chloride (250 μL, 2.87 mmol) and DMF (1 drop) in DCM (10mL) was stirred at rt for 2 h.4-(2-(2-tert-butylphenoxy)pyridin-3-yl)thiosemicarbazide (Example 1b)(908 mg, 2.87 mmol) was added and mixture was stirred for 2 h at 20° C.The reaction mixture was evaporated, diluted in concentrated sulfuricacid and stirred at rt for 2 h. The reaction mixture was cooled to 0° C.and water was added. The solid formed was isolated by filtration,diluted in ethyl acetate and washed with saturated sodium bicarbonate.The organic phase was separated, dried (MgSO₄), filtered and evaporated.The crude material was purified by flash chromatography on silica gel(50% EtOAc/Hexanes) to give Example 96 (600 mg) as a white solid.

(M+H)⁺=455. ¹H NMR (400 MHz, DMSO d₆) δ ppm 1.29 (s, 9 H), 1.70-1.85 (m,3H), 2.05-2.15 (m, 3H), (m, 2H), 3.05-3.20 (m, 2H), 3.60-3.70 (m, 2H),4.50 (s, 3H), 6.91 (dd, J=7.83, 1.26 Hz, 1 H), 7.17 (t, J=5.81, 2H),7.24 (td, J=7.58, 1.52, 1H), 7.44 (dd, J=7.83, 1.52, 1H), 7.81 (dd,J=4.80, 1.52, 1H), 8.83 (dd, J=8.08, 1.52 Hz, 1H), 11.06 (s, 1 H).

Example 97N-Benzyl4-(5-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-1,3,4-thiadiazol-2-yl)-N,4-dimethylpentanamide

Example 97a4-(5-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-1,3,4-thiadiazol-2-yl)-4-methylpentanoicacid

A mixture of methyl4-(5-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-1,3,4-thiadiazol-2-yl)-4-methylpentanoate(Example 96) (450 mg, 1.0 mmol), lithium hydroxide hydrate (125 mg, 3mmol) in THF (10 mL) and water (2 mL) was stirred at rt for 2 h. Asolution of saturated ammonium chloride was added and mixture wasextracted twice using ethyl acetate. The organic phase was separated,dried (MgSO₄), filtered and evaporated. The crude material was purifiedby preparative HPLC to give the title compound (430mg, TFA salt) as awhite solid.

(M+H)⁺=441.

Example 97

A mixture of Example 97a (175 mg, 0.40 mmol), TBTU (193 mg, 0.6 mmol)and N-benzylmethylamine (52 μL, 0.4 mmol) in DMF (4 mL) was stirred atrt for 2 h. The reaction mixture was purified by preparative HPLC togive Example 97 (40 mg, TFA salt) as a white powder. (M+H)⁺=544; ¹H NMR(400 MHz, DMSO d₆) δ ppm 1.29 (s, 9 H), 1.30 (s, 3H), 1.38 (s, 3H),1.90-2.00 (m, 2H), 2.20-2.35 (m, 7 H), 2H), 2.85 (s, 3H), 4.46 (s, 2H),6.90 (dd, J=7.83, 1.52 Hz, 1 H), 7.05-7.35 (m, 7 H), 7.41 (dt, J=7.83,2.02, 1H), 7.68 (dd, J=4.80, 1.76 Hz, 1 H), 8.76 (t, J=6.32 Hz, 1H),10.19 (s, 1 H).

Examples 98 and 99 listed in Table 2 were prepared following theprocedure described for Example 97.

Example 100N-(5-(5-(Benzyl(methyl)amino)-2-methylpentan-2-yl)-1,3,4-thiadiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

A mixture ofN-benzyl-4-(5-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-1,3,4-thiadiazol-2-yl)-N,4-dimethylpentanamide(Example 97) (38 mg, 0.058 mmol), diisobutyl aluminiumhydride (290 μL,1.0 M/hexanes, 0.29 mmol) in THF (2 mL) was stirred at rt for 2 h. Asolution of 1.0 M sodium potassium tartrate was added and mixture wasextracted twice using ethyl acetate. The organic phase was separated,dried (MgSO₄), filtered and evaporated. The crude material was purifiedby preparative HPLC to give Example 100 (11 mg, TFA salt) as a whitesolid. (M+H)⁺=530. ¹H NMR (400 MHz, DMSO d₆) δ ppm 1.29 (s, 9 H), 1.37(s, 6H), 1.55-1.70 (m, 4H), 2.60-2.70 (m, 2H), 2.95 (m, 1H), 3.06 (m,1H), 4.20 (dd, J=12.89, 6.06 Hz, 1 H), 4.38 (dd, J=12.38, 3.79 Hz, 1 H),6.90 (dd, J=6.57, 1.26 Hz, 1 H), 7.12 (dd, J=5.05, 8.08 Hz, 1 H), 7.15(dd, J=7.58, 1.52 Hz, 1 H), 7.21 (dd, J=7.83, 1.77 Hz, 1 H), 7.43 (dd,J=7.83, 1.52 Hz, 1 H), 7.40-7.50 (m, 4H), 7.70 (dd, J=4.80, 1.77, 1H),8.80 (dd, J=7.83, 1.26 Hz, 1 H), 9.32 (m, 1H), 10.25 (s, 1 H).

Example 101 listed in Table 2 was prepared following the proceduredescribed for Example 100.

Example 102N-(5-(3-(Benzyl(methyl)amino)propyl)-1,3,4-thiadiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

Example 102aN-(5-(3-Bromopropyl)-1,3,4-thiadiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

Example 102a was synthetized following the procedure for Example 1 using4-(2-(2-tert-butylphenoxy)pyridin-3-yl)thiosemicarbazide (Example 1b)with 4-bromobutanoyl chloride.

Example 102

A mixture of Example 102a (100 mg, 0.22 mmol), N-benzylmethylamine (115μL, 0.89 mmol) in DMF (4 mL) was heated at 120° C. for 5 min in amicrowave oven (personal chemistry). The crude material was purified bypreparative HPLC to give Example 102 (22 mg, 2 TFA salt) as a whitesolid.

(M+H)⁺=488. ¹H NMR (400 MHz, DMSO d₆) δ ppm 1.30 (s, 9 H), 2.05-2.25 (m,2H), 2.70 (d, J=4.80 Hz, 3H), 3.00 (t, J=6.80 Hz, 2H), 3.05-3.30 (m,2H), 4.24 (dd, J=12.88, 6.32 Hz, 1 H), 4.42 (dd, J=12.38, 4.04 Hz, 1 H),6.92 (dd, J=9.10, 1.01 Hz, 1 H), 7.12 (dd, J=8.09, 4.80 Hz, 1 H), 7.15(dd, J=7.83, 6.32 Hz, 1 H), 7.22 (dt, J=7.58, 1.51 Hz, 1 H) 7.40-7.55(m, 5H), 7.69 (dd, J=4.80, 1.52, 1H), 8.78 (d, J=9.10 Hz, 1 H), 9.54 (m,1H), 10.25 (s, 1 H).

Examples 103-105 listed in Table 2 were prepared following the proceduredescribed for Example 102.

Example 106N-(5-(1-Benzyl-4-methylpiperidin-4-yl)-1,3,4-thiadiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

Example 106a2-(2-tert-Butylphenoxy)-N-(5-(4-methylpiperidin-4-yl)-1,3,4-thiadiazol-2-yl)pyridin-3-amine

A mixture of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylicacid (1.15 g, 4.74 mmol), oxalylchloride (4.13 μL, 4.74 mmol),diisopropylethylamine (1.67 mL, 9.48 mmol) and DMF (1 drop) in DCM (10mL) was stirred at rt for 30 min.4-(2-(2-tert-butylphenoxy)pyridin-3-yl)thiosemicarbazide (Example 1b)(1.5 g, 4.74 mmol) was then added and mixture was stirred for 30 min at20° C. The reaction mixture was evaporated, diluted in concentratedsulfuric acid and stirred at rt for 30 min. The reaction mixture wascooled to 0° C. and water was added. The reaction mixture was diluted inethyl acetate and washed with saturated sodium bicarbonate. The organicphase was separated, dried (MgSO₄), filtered and evaporated. The crudematerial was purified by preparative HPLC to give Example 106a (350 mg)as a white solid. (M+H)⁺=424.

Example 106

A mixture of Example 106a (15 mg, 0.35 mmol), benzaldehyde (3.5 μL, 0.35mmol), acetic acid (50 μL), trimethylorthoformate (0.5 mL), and DMF (0.5mL) was stirred at rt for 18 h. Sodium borohydride (4 mg, 1.05 mmol) wasadded and mixture was stirred for 2 h. The reaction mixture was purifiedby preparative HPLC to give Example 106 (8 mg, 2 TFA salt) as a white.(M+H)⁺=460. ¹H NMR (400 MHz, DMSO d₆) δ ppm (rotomere mixture) 1.30-1.4(m, 9 H), 1.85-2.45 (s, 5H), 3.00-3.15 (m, 4H), 3.25-3.40 (m, 4H), 4.30(d, J=5.30 Hz, 0.6 H), 4.41 (d, J=5.30 Hz, 1.4 H), 6.90 (d, J=7.83 Hz, 1H), 7.10-7.35 (m, 3 H), 7.40-7.55 (m, 5H), 7.65-7.70 (m, 1H), 7.74 (d,J=8.09, 0.3H), 7.84 (d, J=8.9Hz, 0.7H), 9.27 (s, 0.7H), 9.36 (s, 0.3H),10.28 (s, 0.3), 10.41 (s, 0.7 H).

Examples 107-125 listed in Table 2 were prepared following the proceduredescribed for Example 106.

Example 126N-(3-(1-Benzylpiperidin-4-yl)-1,2,4-thiadiazol-5-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

Example 126a 1-Benzylpiperidine-4-carboxamidine

A mixture of ammonium chloride (216 mg, 4.04 mmol), trimethylaluminium(2.02 mL, 2.0M/toluene, 4.04 mmol), in toluene (5 mL) was stirred at rtfor 30 min. Ethyl 1-benzylpiperidine-4-carboxylate (500 mg, 2.02 mmol)was added and mixture was stirred for 18 h at 80° C. The reactionmixture was cooled down and 1N sodium potassium tartrate solution wasadded. The reaction mixture was extracted with ethyl acetate, theorganic phase was separated, dried (MgSO₄), filtered and evaporated. Thecrude material was purified by preparative HPLC to give Example 126a(I120 mg) as a white solid. (M+H)⁺=218.

Example 126

A mixture of Example 126a (120 mg, 0.55 mmol),2-(2-tert-butylphenoxy)-3-isothiocyanatopyridine (Example 1a) (157 mg,0.55 mmol), in DMF (5 mL) was stirred at rt for 2 h.Diethylazodicarboxylate (87 μL, 0.55 mmol) was added and mixture wasstirred for 1 h. The reaction mixture was purified by preparative HPLCto give Example 126 (9 mg, 2 TFA salt) as a white solid. (M+H)⁺=500. ¹HNMR(400 MHz, MeOD d₄) δ ppm 1.35 (s, 9 H), 2.00-2.50(m, 5H),3.10-3.25(m, 2H), 3.62 (d, J=12.38 Hz, 2H), 6.88 (d, J=9.34 Hz, 1 H), 7.09 (dd,J=8.08, 5.05, 1H), 7.15-7.25 (m, 3 H), 7.45-7.55 (m, 5H), 7.72 (dd,J=5.05, 1.52 Hz, 1H), 8.85 (dd, J=8.08, 1.77 Hz, 1H).

Example 1272-(2-tert-Butylphenoxy)-N-(5-(4-(trifluoromethyl)phenyl)isoxazol-3-yl)pyridin-3-amine

Example 127a(Z)-3-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-3-(methylthio)-1-(4-(trifluoromethyl)phenyl)prop-2-en-1-one

To a solution of 1-(4-(trifluoromethyl)phenyl)ethanone (2 g, 10.63 mmol)in DMF (45 mL) at 0° C. was added portionwise the sodium hydride (60%dispersion in mineral oil, 425 mg, 10.63 mmol). After 30 min,2-(2-tert-butylphenoxy)-3-isothiocyanatopyridine (Example 1a) (3.02 g,10.63 mmol) was added and the mixture was allowed to warm to 23° C.After 16 h, iodomethane (0.73 mL, 11.69 mmol) was added and the mixturewas stirred for 24 h. Ethyl acetate (100 mL) and water (100 mL) wereadded and the layers were separated. The organic layer was washed withbrine (100 mL), dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica, 10-40%EtOAc/hexane gradient) providing 2.1 g (45%) of Example 127a as anorange solid. (M+H)⁺=487. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.49 (s, 1H), 8.13 (d, 2H, J=8.1 Hz), 8.02 (t, 1H, J=1.8 Hz), 8.01 (s, 1H), 7.82(d, 2H, J=8.3 Hz), 7.38 (dd, 1H, J=7.8, 1.5 Hz), 7.25-7.12 (m, 3H), 6.98(dd, 1H, J=8.1, 1.3 Hz), 6.14 (s, 1H), 2.60 (s, 3H), 1.26 (s, 9H).

Example 127

In a 10 mL resealable tube, hydroxylamine (50% solution in water, 50 μL,0.823 mmol) and 1 drop of acetic acid were added to Example 127a (100mg, 0.206 mmol) in ethyl alcohol (1 mL). The tube was sealed with aTeflon® cap and the mixture was heated at 85° C. for 6 h. The residuewas purified by preparative HPLC to yield 15 mg (16%, TFA salt) ofExample 127. (M+H)⁺=454. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.91 (s, 1H),8.06 (d, 2H, J=8.1 Hz), 7.93 (dd, 1H, J=7.9, 1.5 Hz), 7.86 (d, 2H, J=8.3Hz), 7.77 (dd, 1H, J=4.8, 1.3 Hz), 7.40, (dd, 1H, J=8.1, 1.8 Hz), 7.22,(td, 1H, J=7.5, 1.5 Hz), 7.16-7.11 (m, 2H), 6.94 (dd, 1H, J=8.1, 1.2Hz), 6.31 (s, 1H), 1.28 (s, 9H).

Examples 128-131 listed in Table 4 were prepared following the proceduredescribed for Example 127. TABLE 4

Example R^(1d) (M + H)⁺ 127 4-CF₃-Ph 454 128 Ph 386 129 pyridin-3-yl 387130 pyridin-4-yl 387 131 —CH(OMe)₂ 384

Example 132N-(3-(4-Bromo-2-fluorophenyl)isoxazol-5-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

Example 132a (E)-4-Bromo-2-fluorobenzaldehyde oxime

To a solution of 4-bromo-2-fluorobenzaldehyde (6 g, 29.6 mmol) in ethylalcohol (50 mL) at 23° C. was added hydroxylamine hydrochloride (3.75 M,9.5 mL, 35.5 mmol) followed by aqueous solution of sodium acetate (1.50M, 15.8 mL, 23.6 mmol). After 5 h, the reaction mixture was concentratedin vacuo. The residual solid was washed with water (50 mL), filtered,toluene was added and the suspension was concentrated in vacuo affording5.43 g (84%) of Example 132a as a white solid.

(M+H)⁻=217. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.81 (s, 1H), 8.16 (s, 1H),7.84 (dd, 1H, J=6.4, 2.5 Hz), 7.65-7.55 (m, 1H), 7.28 (dd, 1H, J=10.1,9.0 Hz).

Example 132b (Z)-4-Bromo-2-fluorobenzoyl chloride oxime

To a solution of Example 132a (5.43 g, 24.9 mmol) in chloroform (62 mL)at 0° C. was added N-chlorosuccinimide (3.66 g, 27.4 mmol) followed bythe pyridine (20 μL, 0.24 mmol) and the mixture was allowed to reach 23°C. After 4 h, the reaction mixture poured into a mixture of water andethyl acetate, layers were separated. The organic layer was washed withwater (twice), brine, dried over Na₂SO₄ and concentrated in vacuoaffording 6.28 g (100%) of Example 132b as a beige solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 12.79 (s, 1H), 7.82 (dd, 1H, J=6.3 2.5 Hz),7.77-7.73 (m, 1H), 7.36 (dd, 1H, J=10.3, 8.9 Hz).

Example 132c 3-(4-Bromo-2-fluorophenyl)-5-chloroisoxazole

To a solution of Example 132b (6.28 g, 24.9 mmol) in1,1-dichloroethylene (39 mL) at 23° C. was added dropwise a solution oftriethylamine (8.7 mL, 62.2 mmol) in 1,1-dichloroethylene (39 mL). After4 h, the reaction mixture was poured into a mixture of water and ethylacetate and the layers were separated. The organic layer was washed withwater (twice), dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by flash chromatography (silica gel, 5%EtOAc/hexanes) providing 2.69 g (39%) of Example 132c as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.02 (dd, 1H, J=6.3, 2.5 Hz), 7.83-7.79(m, 1H), 7.44 (dd, 1H, J=10.6, 8.8 Hz), 7.26 (d, 1H, J=2.3 Hz).

Example 132

To a solution of 2-(2-tert-Butylphenoxy)-3-aminopyridine(Intermediate 1) (4.38 g, 18.08 mmol) in THF (30 mL) at 0° C. was addeddropwise a solution of n-butyllithium (11.3 mL, 18.08 mmol) in hexanes.After 20 min, Example 132c (2.5 g, 9.04 mmol) was added, the mixture wasallowed to reach 23° C. and stirred at 23° C. for 60 h. The reactionmixture was quenched with a saturated s solution of ammonium chloride(30 mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with water (150 mL), brine (150 mL), dried overNa₂SO₄ and concentrated in vacuo. The crude material was purified byflash chromatography (silica gel, 10% EtOAc/hexanes) providing 1.97 g(45%) of Example 132. (M+H)⁺=482. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.92(s, 1H), 8.00 (dd, 1H, J=6.3, 2.5 Hz), 7.92 (dd, 1H, J=7.8, 1.8 Hz),7.77 (dd, 1H, J=4.8, 1.6 Hz), 7.77-7.72 (m, 1H), 7.42-7.37 (m, 2H),7.22, (td, 1H, J=7.3, 1.5 Hz), 7.15-7.11 (m, 2H), 6.93 (dd, 1H, J=8.1,1.3 Hz), 6.10 (s, 1H), 1.28 (s, 9H).

Examples 133-134 listed in Table 5 were prepared following the proceduredescribed for Example 132. TABLE 5

Example R^(1d) (M + H)^(′) 132 2-F-4-Br-Ph 482 133 Ph 386 134 3-CH₂OH-Ph416 135 2-F-4-(piperidin-1-yl)-Ph 487 136 2-F-4-(azepan-1-yl)-Ph 501 1372-F-4-(pyrrolidin-1-yl)-Ph 473 138 2-F-4-(2-CH₂NMe₂-Ph)-Ph 537 1392-F-4-(4-Bn-piperazin-1-yl)-Ph 577 140 CO₂Et 382 141 3-NO₂-Ph 431 1424-SO₂Me-Ph 464 143 2-Cl-Ph 420 144 2,4-diMe-Ph 414 145benzo[b]thien-3-yl 442 146 3-Ph-isoxazol-5-yl 453 147 3-CN-Ph 411 1483-Me-4-Cl-Ph 434 149 3-NO₂-4-Cl-Ph 465 150 naphth-2-yl 436 1513,4-diCl-Ph 455 152 4-NO₂-Ph 431 153 4-CN-Ph 411 154 4-Ph-Ph 462 1553-F-Ph 404 156 2-F-4-Cl-5-Me-Ph 452 157 2-F-Ph 404 158 4-cyclohexyl-Ph468 159 3-Ph-5-Me-isoxazol-4-yl 467 160 5-Ph-thien-2-yl 468 1611,3-benzodioxol-4-yl 430 162 3-CH₂N(Me)Bn-Ph 519 1633-(CH₂-piperidin-1-yl)-Ph 483 164 3-(CH₂-morpholin-4-yl)-Ph 485 1653-(CH₂-1,2,3,4- 531 tetrahydroisoquinolin-2-yl)-Ph 1663-(CH₂-4-Me-piperazin-1-yl)-Ph 498 167 3-CH₂NMe₂-Ph 443 1683-(CH₂-piperazin-1-yl)-Ph 484 169 CON(Me)Bn 457 170 —CH₂N(Me)Bn 443 1714-(1H-tetrazol-5-yl)-Ph 454

Example 1352-(2-tert-Butylphenoxy)-N-(3-(2-fluoro-4-(piperidin-1-yl)phenyl)isoxazol-5-yl)pyrindin-3-amine

A 15-mL oven-dried resealable flask capped with a rubber septum wasevacuated and backfilled with argon. The flask was charged withN-(3-(4-bromo-2-fluorophenyl)isoxazol-5-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine(Example 132) (35 mg, 0.073 mmol), sodium tert-butoxide (10 mg, 0.102mmol), Pd₂(dba)₃ (3 mg, 0.003 mmol), (o-biphenyl)PCy₂ (2.1 mg, 5.24mmol) and evacuated and backfilled with Argon. Toluene (0.72 mL) andpiperidine (8.6 μL, 0.087 mmol) were added and argon was bubbled throughthe mixture for 20 min. The septum was replaced with a Teflon® screwcap,the flask was sealed and the mixture was heated at 80° C. for 16 h. Themixture was cooled to rt, filtered through Celite® and concentrated invacuo. The residue was purified by preparative HPLC to yield 10 mg (30%,TFA salt) of Example 135. (M+H)⁺=487. ¹H NMR (400 MHz, DMSO-d₆) δ ppm9.85 (s, 1H), 7.90 (dd, 1H, J=7.8, 1.7 Hz), 7.76 (dd, 1H, J=4.8, 1.5Hz), 7.40 (dd, 1H, J=8.1, 1.8 Hz), 7.26-7.34 (m, 1H), 7.22, (td, 1H,J=7.6, 1.7 Hz), 7.10-7.16 (m, 3H), 6.93 (dd, 1H, J=8.1, 1.6 Hz), 6.03(d, 1H, J=3.0 Hz), 3.22 (m, 4H), 1.69 (m, 4H), 1.56 (m, 2H), 1.28 (s,9H).

Examples 136-139 listed in Table 5 were prepared following the proceduredescribed for Example 135.

Example 140 Ethyl5-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)isoxazole-3-carboxylate

Example 140a 2-(2-tert-Butylphenoxy)-3-isocyanopyridine

Example 140a was prepared according to the procedure described by Bartonet al. (Tetrahedron, 1988, 44, 3501-3512) using2-(2-tert-butylphenoxy)pyridin-3-amine (Intermediate 1) (1 g, 4.12 mmol)affording 696 mg (67%) of the title compound. (M+H)⁺=253.

Example 140b Ethyl 3-Bromo-2-(hydroxyimino)propanoate

Example 140b was prepared according to the procedure described by Bogeret al. in J. Am. Chem. Soc, 1991, 113(5), 1713-1729.

Example 140

To a solution of Example 140b (55 mg, 0.26 mmol) in DCM (1.3 mL) wasadded a solution of Example 140a (1M in DCM, 524 μL, 0.52 mmol) andsodium carbonate (56 mg, 0.52 mmol). The mixture was stirred for 16 h,then filtered and concentrated in vacuo. The residue was purified bypreparative HPLC to yield 20 mg (20% TFA salt) of Example 140.(M+H)⁺=382. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.89 (dd, 1H, J=7.8, 1.5Hz), 7.78 (dd, 1H, J=4.8, 1.5 Hz), 7.39 (dd, 1H, J=8.1, 1.8 Hz), 7.22,(td, 1H, J=7.6, 1.8 Hz), 7.10-7.15 (m, 2H), 6.93 (dd, 1H, J=8.1, 1.6Hz),5.92 (d, 1H, J=3.7Hz), 4.32 (q, 2H, J=7.0Hz), 1.29 (t, 3H, J=7.3 Hz),1.26 (s, 9H).

Examples 141-161 listed in Table 5 were prepared following the proceduredescribed for Example 140.

Example 162N-(3-(3-((Benzyl(methyl)amino)methyl)phenyl)isoxazol-5-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

Example 162a3-(5-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)isoxazol-3-yl)benzaldehyde

To a solution of(3-(5-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)isoxazol-3-yl)phenyl)methanol(378 mg, 0.91 mmol) in DCM (10 mL) was added Dess-Martin periodinane(424 mg, 1.00 mmol). The mixture was stirred at 23° C. for 15 min, thenconcentrated in vacuo. Ethyl acetate was added, washed with a saturatedaqueous bicarbonate solution, 10% aqueous solution of sodiumthiosulfate, water and brine, dried over Na₂SO₄ and concentrated invacuo. The crude material was purified by flash chromatography (silicagel, 30-50% EtOAc/hexane gradient) providing 328 mg (87%) of Example162a. (M+H)⁺=414.

Example 162

To a solution of Example 162a (20 mg, 0.048 mmol) in DMF (0.5 mL) wasadded N-methyl(phenyl)methanamine (17 mg, 0.14 mmol), acetic acid (12.5μL) and trimethylorthoformate (0.5 mL). The reaction mixture was shakenfor 16 h then, sodium borohydride (5.5 mg, 0.14 mmol) was added andafter 3 h, then a 50% aqueous solution of methanol was added and themixture was concentrated in vacuo. The residue was purified bypreparative HPLC.) to yield 6.6 mg (18% TFA salt) of Example 162.(M+H)⁺=519.

Examples 163-168 listed in Table 5 were prepared following the proceduredescribed for Example 162.

Example 169N-Benzyl-5-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-N-methylisoxazole-3-carboxamide

Under Argon atmosphere, in a resealable tube equipped with a septum, atrimethylaluminium solution (2M in toluene, 157 μL, 0.31 mmol) was addedto methylbenzylamine (40 μL, 0.31 mmol) in toluene at 0° C. The mixturewas allowed to reach r.t. and after 1 h, ethyl5-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)isoxazole-3-carboxylate (60mg, 0.16 mmol) was added, the septum was replaced by a Teflon® cap,sealed and heated at reflux for 2 h. The mixture was cooled to r.t,neutralized with 1N HCl solution, extracted with ethyl acetate. Thecombined organic layers were washed with water, brine, dried over Na₂SO₄and concentrated in vacuo. The residue was purified by preparative HPLCto yield 35 mg (48% of the TFA salt) of Example 169. (M+H)⁺=457. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 9.95 (s, 1H, rotamer A), 9.93 (s, 1H, rotamerB), 7.90-7.85 (m, 2H, rotamers), 7.77-7.75 (m, 2H, rotamers), 7.40-7.19(m, 12H, rotamers), 7.15-7.07 (m, 4H, rotamers), 6.94-6.91 (m, 2H,rotamers), 5.85 (s, 1H, rotamer A), 5.80 (s, 1H, rotamer B), 4.67 (s,2H, rotamer A), 4.66 (s, 2H, rotamer B), 3.00 (s, 3H, rotamer B), 2.85(s, 3H, rotamer A), 1.27 (s, 9H, rotamer A), 1.27 (s, 9H, rotamer B).

Example 170N-(3-((Benzyl(methyl)amino)methyl)isoxazol-5-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

To a solution ofN-benzyl-5-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-N-methylisoxazole-3-carboxamide(Example 169) (18.7 mg of TFA salt, 0.033 mmol) in THF (1 mL) was addedlithium aluminium hydride (2 mg, 0.053 mmol) and the mixture was stirredat rt for 16 h. The mixture was quenched with Rochelle's salt solutionand extracted with ethyl acetate. Combined organic layers were washedwith water, brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by preparative HPLC to yield 6 mg (41% of the TFAsalt) of Example 170. (M+H)⁺=443. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.34(broad s, 1H, rotamer A), 10.00 (broad s, 1H, rotamer B), 7.88 (dd, 1H,J=7.8, 1.5 Hz), 7.78 (dd, 1H, J=4.8, 1.5 Hz), 7.55-7.45 (broad m, 5H),7.39 (dd, 1H, J=8.1, 1.8 Hz), 7.22, (td, 1H, J=7.6, 1.8 Hz), 7.16-7.09(m, 2H), 6.93 (dd, 1H, J=8.1, 1.6 Hz), 5.83 (s, 1H), 4.50-4.25 (broad m,4H), 2.68 (broad s, 3H), 1.27 (s, 9H).

Example 171N-(3-(4-(1H-Tetrazol-5-yl)phenyl)isoxazol-5-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

To a solution of4-(5-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)isoxazol-3-yl)benzonitrile(Example 153) (120 mg, 0.29 mmol) in DMF (1.3 mL) was added sodium azide(21 mg, 0.32 mmol) and ammonium chloride (17 mg, 0.32 mmol) and themixture was stirred at 100° C. for 4 days. The residue was purified bypreparative HPLC to yield 0.92 mg (0.6% of the TFA salt) of Example 171.

(M+H)⁺=454.

Example 1721-Benzyl-3-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-1H-pyrazole-5-carbonitrile

Example 172a 1,1-Dimethoxy-4,4-bis(methylthio)but-3-en-2-one

Example 172a was prepared following the procedure described by Mahata etal. in Tetrahedron, 2003, 59, 2631-3639.

Example 172b(Z)-4-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-1,1-dimethoxy-4-(methylthio)but-3-en-2-one

Example 172b was prepared, following the procedure described for Example132, using 2-(2-tert-butylphenoxy)pyridin-3-amine (Intermediate 1) (4.30g, 17.8 mmol), Example 172a (3.29 g, 14.8 mmol), n-butyllithium (765 μL,5.48 mmol) and THF (105 mL) as a tan solid (4.04 g, 66%). (M+H)⁺=417.

Example 172c2-(2-tert-Butylphenoxy)-N-(5-(dimethoxymethyl)-1H-pyrazol-3-yl)pyridin-3-amine

To a solution of Example 172b (2.5 g, 6.0 mmol) in ethanol (12 mL) wasadded hydrazine hydrate (280 μL, 9.0 mmol). The mixture was heated atreflux for 2 h, allowed to cool down, concentrated in vacuo.Dichloromethane was then added and the mixture was washed with water,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash chromatography (silica gel, 40% EtOAc/hexanes) to provide 2.07 g(90%) of Example 172c. (M+H)⁺=383.

Example 172dN-(1-(4-Methoxybenzyl)-5-(dimethoxymethyl)-1H-pyrazol-3-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

To a solution of Example 172c (1.31 g, 3.42 mmol) in THF (17 mL) wasadded 4-methoxybenzylalcohol (854 μL, 6.85 mmol), tributylphosphine(1.71 mL, 6.85 mL) and 1,1′-azobisdimethylformarnide (1.18 g, 6.85mmol). The mixture was stirred at 23° C. for 28 h, filtered, washed withTHF and the filtrate was concentrated in vacuo. The residue was purifiedby flash chromatography (silica gel, 25-40% EtOAc/hexanes) to provide792 mg (46%) of Example 172d. (M+H)⁺=503.

Example 172e1-(4-Methoxybenzyl)-3-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-1H-pyrazole-5-carbaldehyde

To a solution of Example 172d (782 mg, 1.55 mmol) in THF (8 mL) wasadded a 50% aqueous solution of acetic acid (20 mL). After 24 h, themixture was neutralized carefully with an aqueous solution of sodiumbicarbonate, extracted with chloroform (3×). The combined organic layerswere washed with water, dried over Na₂SO₄ and concentrated in vacuo togive 657 mg (92%) of Example 172e.

(M+H)⁺=457.

Example 172f1-(4-Methoxybenzyl)-3-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-1H-pyrazole-5-carbaldehydeoxime

To a solution of Example 172e (492 mg, 1.08 mmol) in ethanol (2.15 mL)was added hydroxylamine hydrochloride (150 mg, 2.16 mmol). The mixturewas stirred at 23° C. for 21 h, then concentrated in vacuo, water wasadded and the separated aqueous layer was extracted with ethyl acetate(3×). The combined organic layers were washed with a saturated aqueoussolution of sodium bicarbonate, water, dried over Na₂SO₄ andconcentrated in vacuo to afford 500 mg (99%) of Example 172f.(M+H)⁺=472.

Example 172g1-(4-Methoxybenzyl)-3-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-1H-pyrazole-5-carbonitrile

To a solution of Example 172f (500 mg, 1.06 mmol) in diethyl ether (5.3mL) was added thionyl chloride (155 μL, 2.12 mmol) at 0° C. The mixturewas allowed to reach 23° C. and stirred for 2 h, water was added and theseparated aqueous layer was extracted with ethyl acetate (3×). Thecombined organic layers were washed with water, brine, dried over Na₂SO₄and concentrated in vacuo. The residue was purified by flashchromatography (silica gel, 15-30% EtOAc/hexane) to provide 334 mg (70%)of Example 172g. (M+H)⁺=454.

Example 172h3-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-1H-pyrazole-5-carbonitrile

Example 172g (238 mg, 0.52 mmol) was placed in a microwave vessel andtrifluoroacetic acid (5 mL) was added. The mixture was heated for 5 min.at 100° C., then cooled to 23° C. and concentrated in vacuo. Ethylacetate was added, washed with a saturated aqueous solution of sodiumbicarbonate, dried over Na₂SO₄ and concentrated in vacuo. The residuewas purified by flash chromatography (silica gel, 20% EtOAc/hexanes) toafford 160 mg (93%) of Example 172h. (M+H)⁺=334.

Example 172

To a solution of Example 172h (20 mg, 0.076 mmol) in THF (1 mL) wasadded benzylalcohol (12 μL, 0.120 mmol), tributylphosphine (30 mL, 0.12mmol) and 1,1′-azobisdimethylformamide (21 mg, 0.12 mmol). The mixturewas stirred at 23° C. for 21 h, filtered, washed with THF and thefiltrate was concentrated in vacuo. The residue was purified bypreparative HPLC to yield 3 mg (12% TFA salt) of Example 172.(M+H)⁺=424. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.74 (s, 1H), 8.34 (dd, 1H,J=7.8, 1.8 Hz), 7.50 (dd, 1H, J=4.8, 1.5 Hz), 7.41-7.38 (m, 3H), 7.33(tt, 1H, J=7.3, 2.6 Hz), 7.27 (dd, 2H, J=8.4, 1.6 Hz), 7.21 (td, 1H,J=7.5, 1.5 Hz), 7.13 (td, 1H, J=7.3, 1.5 Hz), 7.00 (dd, 1H, J=7.8, 4.8Hz), 6.88 (dd, 1H, J=8.1, 1.5 Hz), 6.84 (s, 1H), 1.30 (s, 9H).

Examples 173-188 listed in Table 6 were prepared following the proceduredescribed for Example 172. TABLE 6

Example R¹¹ R^(2d) (M + H)⁺ 172 Bn CN 424 173 phenethyl CN 438 174—(CH₂)₂-indol-3-yl CN 477 175 —(CH₂)₂-thien-2-yl CN 444 176—(CH₂)₂-pyridin-2-yl CN 439 177 —(CH₂)₂-pyridin-4-yl CN 439 178—(CH₂)₂-(4-Me-thiazol-5-yl) CN 459 179 —(CH₂)₂SMe CN 408 180 —(CH₂)₂OMeCN 392 181 neohexyl CN 418 182 —CH₂CHC(Me)₂ CN 402 183 —CH₂-cyclopropylCN 388 184 n-Bu CN 390 185 3-Bn CN 492 186 Bn Ph 475 187 —(CH₂)₃N(Me)₂2-F-Ph 488 188 phenethyl 2-F-Ph 507 189 Me Ph 399 191 Me 2-F-Ph 417 192Me 4-CF₃-Ph 467 194 H Ph 385 197 Me CN 348 198 Et Ph 413 199 phenethylCONMe₂ 484 202b Ph CN 410 477 —CH₂-thien-2-yl CN 430 478 2-F-6-Cl-Bn CN477 479 —CHMe-furan-2-yl CN 428 480 2-Cl-Bn CN 459 481 2-Cl-4-F-Bn CN477 482 2-Br-Bn CN 503 483 —CHMe-Ph CN 438 484 —(CH₂)₂S(i-Pr) CN 436 485—(CH₂)₂SEt CN 422 486 —(CH₂)₃SMe CN 422 487 3-Cl-Bn CN 459 488 4-SMe-BnCN 470 489 4-Cl-phenethyl CN 473 490 —(CH₂)₂O(4-Cl-Ph) CN 489 4913,5-diCl-Bn CN 493 492 4-Br-Bn CN 503 493 —(CH₂)₂O(CH₂)₂Cl CN 441 4942-F-4-Br-Bn CN 521 495 —(CH₂)₂-thien-3-yl CN 444

Example 189 & 190 Example 1892-(2-tert-butylphenoxy)-N-(1-methyl-5-phenyl-1H-pyrazol-3-yl)pyridin-3-amineExample 1902-(2-tert-butylphenoxy)-N-(1-methyl-3-phenyl-1H-pyrazol-5-yl)pyridin-3-amine

Example 189aN-(2-(2-tert-Butylphenoxy)pyridin-3-yl)-3-oxo-3-phenylpropanethioamide

To a solution of acetophenone (123 μL, 1.05 mmol) in THF (4.4 mL) at−78° C. was added the solution of LiHMDS (1M/THF, 1.14 mL, 1.30 mmol).After 30 min, 2-(2-tert-butylphenoxy)-3-isothiocyanatopyridine (Example1a) (250 mg, 1.00 mmol) was added and the mixture was allowed to reach23° C. After 17 h, ethyl acetate (100 mL) and an aqueous solution ofsaturated ammonium chloride (100 mL) were added and the layers wereseparated. The separated organic layer was washed with water (100 mL),brine (100 mL), dried over Na₂SO₄ and concentrated in vacuo. The crudematerial was purified by trituration in mixture of 10% EtOAc/hexanes toprovide 180 mg (51%) of Example 189a. (M+H)⁺=405.

Examples 189 & 190

Examples 189 and 190 were prepared following the procedure described forExample 127 using Example 189a (22.2 mg, 0.06 mmol) and methylhydrazine(12 μL, 0.22 mmol). Example 189 and 190 were separated by preparativeHPLC (solvent A: 10% acetonitrile−90% water+0.1% TFA; solvent B: 90%acetonitrile−10% water+0.1% TFA, with 20% B to 100% in 7 min gradient.Column: YMC Pack C-18 20×100 mm. Flow rate=20 mL/min.) to yield 10 mg(35%, TFA salt) of Example 190 and 9 mg (32%, TFA salt) of Example 189.Example 190: (M+H)⁺=399. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.87 (s, 1H),7.80 (dd, 2H, J=7.1, 1.2 Hz), 7.50 (dd, 1H, J=4.8, 1.5 Hz), 7.42-7.36(m, 3H), 7.28 (tt, 1H, J=7.3), 7.23, (td, 1H, J=7.3, 1.8 Hz), 7.15-7.11(m, 2H), 6.96-6.92 (m, 2H), 6.65 (s, 1H), 3.71 (s, 3H), 1.34 (s, 9H).Example 189: (M+H)⁺=399. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.49 (dd, 1H,J=7.8, 1.5 Hz), 8.23 (s, 1H), 7.54-7.48 (m, 3H), 7.46-7.40 (m, 3H), 7.21(td, 1H, J=7.6, 1.3 Hz), 7.13 (td, 1H, J=7.9, 1.3 Hz), 6.99 (dd, 1H,J=8.1, 4.8 Hz), 6.89 (dd, 1H, J=8.1, 1.2 Hz), 6.19 (s, 1H), 3.77 (s,3H), 1.33 (s, 9H).

Examples 191-192 and 194 listed in Table 6 and Examples 193 and 195-196listed in Table 7 were prepared using the appropriate commerciallyavailable substituted benzophenone following the procedures describedfor Examples 189 and 190. TABLE 7

Example R¹¹ R^(1d) (M + H)⁺ 190 Me Ph 399 193 H 2-F-Ph 195 Me 2-F-Ph 417196 Me 4-CF₃-Ph 467 202a Ph CN 410

Example 1973-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-1-methyl-1H-pyrazole-5-carbonitrile

To a solution of3-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-1H-pyrazole-5-carbonitrile(Example 172h) (47 mg, 0.141 mmol) in THF (1.4 mL) at 0° C. was addedsodium hydride (60%, 5.6 mg, 0.141 mmol). After 5 min, iodomethane (9μL, 0.141 mmol) was added, the mixture was allowed to reach 23° C. andstirred for 20 h. Saturated NH₄Cl was added and the separated aqueouslayer was extracted with ethyl acetate (2×). The combined organic layerswere washed with water, brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified preparative HPLC to yield 5 mg (10%, TFAsalt) of Example 197. (M+H)⁺=348.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.11 (s, 1 H), 7.58 (dd, 1 H, J=4.8, 1.5Hz), 7.39 (dd, 1H, J=8.1, 1.5 Hz), 7.24-7.17 (m, 3H), 7.12 (td, 1H,J=7.6, 1.5 Hz), 6.95 (dd, 1H, J=6.4, 4.8 Hz), 6.94 (dd, 1H, J=7.8, 1.3Hz), 6.82 (s, 1H), 3.77 (s, 3H), 1.30 (s, 9H).

Example 198 listed in Table 6 was prepared following the proceduredescribed for Example 197.

Example 1993-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-N,N-dimethyl-1-phenethyl-1H-pyrazole-5-carboxamide

Example 199a3-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-1-phenethyl-1H-pyrazole-5-carboxylicacid

To3-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-1-phenethyl-1H-pyrazole-5-carbonitrile(Example 177) (75.6 mg, 0.17 mmol) in methanol (7.2 mL) was added a 1NNaOH solution (2.76 mL, 2.76 mmol) and the mixture was heated at refluxfor 5 h. The mixture was concentrated in vacuo, acidified using 1N HCl(until pH=1) then extracted with ethyl acetate (three times). Thecombined organic layers were washed with water, brine, dried over Na₂SO₄and concentrated in vacuo to afford 14.2 mg (18%) of Example 199a.(M+H)⁺=457.

Example 199

To Example 199a (5.7 mg, 0.012 mmol) in 1 mL of N,N-dimethylformamide,was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiumide (20 mg, 0.104mmol), 1-hydroxybenzotriazole hydrate (15 mg, 0.104 mmol),N,N-dimethylamine (2M in THF, 52 μL, 0.104 mmol) and Hunig's base (36μL, 0.208 mmol). The mixture was stirred for 18 h at 23° C. and water(50 mL) was added. The aqueous layer was extracted with ethyl acetate(3×50 mL) and the combined organic layers were washed with an aqueoussaturated solution of sodium bicarbonate (50 mL), water (50 mL), brine(50 mL) and dried (anh. Na₂SO₄), filtered and concentrated in vacuo. Theresidue was purified preparative HPLC to yield 3 mg (42%, TFA salt) ofExample 199. (M+H)⁺=484. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.32 (dd, 1H,J=8.1, 1.8 Hz), 8.29 (s, 1H), 7.45 (dd, 1H, J=4.8, 1.5 Hz), 7.40 (dd,1H, J=7.8, 1.5 Hz), 7.27-7.17 (m, 5H), 7.14-7.10 (m, 3H), 6.98 (dd, 1H,J=7.8, 4.8 Hz), 6.87 (dd, 1H, J=8.1, 1.5 Hz), 6.12 (s, 1H), 4.39 (t, 2H,J=6.5 Hz), 3.05 (t, 2H, J=6.8 Hz), 2.86 (s, 3H), 2.71 (s, 3H), 1.30 (s,9H).

Example 202a 25-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-1-phenyl-1H-pyrazole-3-carbonitrileExample 202b3-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-1-phenyl-1H-pyrazole-5-carbonitrile

A 15-mL oven-dried re-sealable flask capped with a rubber septum wasevacuated and backfilled with argon. The flask was charged with3-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-1H-pyrazole-5-carbonitrile(Example 172h) (20 mg, 0.076 mmol), phenyl boronic acid (14.5 mg, 0.120mmol), Cu(OAc)₂ (16.3 mg, 0.089 mmol), pyridine (10 μL, 0.120 mmol) andmolecular sieves 4 Å (44 mg) and evacuated and backfilled with Argon.Dichloromethane (1.0 mL) was then added and the septum was replaced witha Teflon® screwcap, the flask was sealed and the mixture was stirred for15 h. The mixture was filtered through Celite® and concentrated invacuo. The residue was purified by preparative HPLC (solvent A: 10%acetonitrile−90% water+0.1% TFA; solvent B: 90% acetonitrile−10%water+0.1% TFA, with 20% B to 100% in 7 min. gradient. Column: YMC PackC-18 20×100 mm. Flow rate=20 mL/min to yield 7.3 mg (14%, TFA salt) ofExample 202a and 6.8 mg (14%, TFA salt) of Example 202b. Example 202a:(M+H)⁺=410. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.16 (s, 1H), 7.64 (dd, 2H,J=7.1, 1.5 Hz), 7.51-7.41 (m, 4H), 7.36 (dd, 1H, J=7.8, 1.5 Hz), 7.20,(td, 1H, J=7.6, 1.5 Hz), 7.13-7.06 (m, 2H), 7.06 (s, 1H), 6.87 (dd, 1H,J=7.9, 7.5 Hz), 6.83 (dd, 1H, J=7.8, 1.3 Hz), 1.24 (s, 9H). Example202b: (M+H)⁺=410. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.98 (s, 1H), 8.49(dd, 1H, J=7.9, 1.6 Hz), 7.77 (d, 2H, J=7.6 Hz), 7.61 (t, 2H, J=8.4 Hz),7.55 (dd, 1H, J=4.6, 1.3 Hz), 7.49 (t, 1H, J=7.3 Hz), 7.42 (dd, 1H,J=7.8, 1.5 Hz), 7.23 (td, 1H, J=7.3, 1.5 Hz), 7.14 (td, 1H, J=7.3, 1.2Hz), 7.12 (s, 1H), 7.04 (dd, 1H, J=7.9, 5.0 Hz), 6.92 (dd, 1H, J=8.1,1.3 Hz), 1.31 (s, 9H).

Example 2032-(2-tert-Butylphenoxy)-N-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridin-3-amine

Example 203a4-(2-(2-tert-Butylphenoxy)pyridin-3-yl)-1-phenylsemicarbazide

A mixture of 2-(2-tert-butylphenoxy)-3-aminopyridine (Intermediate 1)(358 mg, 1.48 mmol), 1,1-carbonylimidazole (239 mg, 1.48 mmol) andbenzoic hydrazide (200 mg, 1.48 mmol) in THF (10 mL) was stirred at roomtemperature for 72 h. Saturated ammonium chloride (15 mL) was added andthe mixture was extracted with ethyl acetate (3×25 mL). The combinedorganic layers were dried (anhydrous sodium sulfate), filtered andevaporated to yield an oily residue which was purified by reverse phasepreparative HPLC to afford Example 203a (75 mg).

(M+H)⁺=405.

Example 203

Hexachloroethane (25 mg, 0.1 mmol) was added to a mixture of Example203a (34 mg, 0.08 mmol), triphenylphosphine (37 mg, 0.14 mmol) andN,N-diisopropylethylamine (73 μL, 0.42 mmol) in acetonitrile (1 mL) andthe mixture was stirred at rt for 1.5 h. The solvent was removed and theresidue was dissolved in ethyl acetate, washed with water, dried(anhydrous sodium sulfate), filtered and evaporated. The residue waspurified by reverse phase preparative HPLC. (M+H)⁺=387; mono-TFA salt:¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31 (s, 9 H), 6.91 (dd, J=8.0, 1.3 Hz,1 H), 7.15-7.23 (m, 3 H), 7.42 (dd, J=7.8, 1.8 Hz, 1 H), 7.58 (m, 3 H),7.81 (dd, J=4.8, 1.5 Hz, 1 H), 7.91 (m, 2 H), 8.50 (dd, J=7.8, 1.5 Hz, 1H), 10.52 (s, 1 H).

Example 2042-(2-tert-Butylphenoxy)-N-(5-phenyl-1,2,4-oxadiazol-3-yl)pyridin-3-amine

Example 204a1-Benzoyl-3-[2-(2-tert-butyl-phenoxy)-pyridin-3-yl]-thiourea

A mixture of 2-(2-tert-Butylphenoxy)-3-aminopyridine (Intermediate 1)(200 mg, 0.82 mmol) and benzoyl isothiocyanate (133 μL, 0.99 mmol, 1.2eq) in DCM (10 mL) was heated at reflux for 1 h. The mixture was cooledto rt and evaporated to give the crude product. Purification by flashchromatography (silica, 0-50% EtOAc/hexane gradient) provided Example204a as a white fluffy powder.

(M+H)⁺=406.29.

Example 204

Sodium hydride (16 mg, 60% oil dispersion, 0.39 mmol) was added to amixture of Example 204a (160 mg, 0.39 mmol) in THF (2.0 mL) and themixture was stirred at rt for 5 min. Iodomethane (27 μL, 0.44 mmol) wasadded and the mixture was stirred at rt for 3 h. The solvent was removedand the residue was dissolved in ethanol. Hydroxylamine hydrochloride(27 mg, 0.39 mmol) was added and the mixture was heated at 75° C. for 16h. The mixture was then allowed to cool and saturated ammonium chloride(30 mL) was added and the mixture was extracted with ethyl acetate (3×25mL). The combined organic layers were dried (anhydrous sodium sulfate),filtered and evaporated to yield an oily residue which was purified byreverse preparative HPLC. (M+H)⁺=387; mono-TFA salt: ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.31 (s, 9 H), 6.90 (dd, J=8.0, 1.3 Hz, 1 H), 7.13-7.22(m, 3 H), 7.40 (dd, J=7.8, 1.8 Hz, 1 H), 7.63-7.75 (m, 2 H), 7.76 (dd,J=4.8, 1.8 Hz, 1 H), 8.09 (m, 2 H), 8.24 (dd, J=7.8, 1.5 Hz, 1 H), 9.58(s, 1 H).

Example 2085-((Benzyl(methyl)amino)methyl)-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)pyridine-2-amine

Example 208a N-((6-Bromopyridin-3-yl)-N-methyl(phenyl)methanamine

To a solution of 6-bromonicotinaldehyde (930 mg, 5.0 mmol) andN-(6-bromopyridin-3-yl)-N-methyl(phenyl)methanamine (727 mg, 6.0 mmol)in dry THF (10 mL) was added NaBH(OAc)₃ (1.59 g, 7.5 mmol) followed byAcOH (300 mg, 5.0 mmol). The reaction was stirred at 25° C. for 16 h andpoured into std NaHCO₃ aqueous solution. The solution was extracted withAcOEt. The organic phase was dried (MgSO₄) and concentrated to givecrude product. Purification by flash chromatography (silica gel, 1:1EtOAc/hexane) provided Example 208a (1.16 g, 80%) as light brown oil.

Example 208b N-Benzyl-6-chloro-N-methylnicotinamide

A solution of N-methyl(phenyl)metanamine (424 mg, 3.5 mmol) and Et₃N(0.98 mL, 7.0 mmol) in CH₂Cl₂ (10 mL) was slowly treated with asuspension of 6-chloronicotinoyl chloride (528 mg, 3.0 mmol) in CH₂Cl₂(10 mL). The reaction was stirred at 23° C. for 1 h and washed with H₂O.The organic phase was dried (MgSO₄) and concentrated to give crudematerial. Purification by flash chromatography (silica, 1:1EtOAc/hexane) provided Example 208b (450 mg, 32%) as thick colorlessoil.

Example 208

To a solution of 2-(2-tert-butylphenoxy)pyridin-3-amine (Intermediate 1)(100 mg, 0.413 mmol) and Example 208a (145 mg, 0.50 mmol) in oxygen-freetoluene (2 mL) was added Nolan catalyst (25 mg) followed by sodiumtert-butoxyde (39 mg, 0.41 mmol). The reaction was stirred at 85° C. for20 h and partitioned between H₂O and AcOEt. The organic phase was dried(MgSO₄) and concentrated to give crude material. Purification by flashchromatography (silica gel, 5-10% CH₃CN/CH₂Cl₂ gradient) providedExample 208 (88 mg, 47%) as a thick oil.

(M+H)⁺=452; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27 (s, 9 H), 2.05 (s, 3H), 3.41 (s, 2 H), 3.47 (s, 2H), 6.93 (dd, J=7.9, 1.3Hz, 1H), 7.03 (dd,J=7.9, 5.0Hz, 7.11 (s, 2H), 7.13 (s, 2H), 7.16-7.27 (m, 2H), 7.32 (s,2H), 7.33 (s, 2H), 7.37 (dd, J=7.8, 1.5 Hz, 1 H), 7.57 (dd, J=8.7, 2.3Hz, 1 H), 7.62 (dd, J=4.8, 1.8 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H), 8.62 (s,1 H), 8.68 (dd, J=7.9, 1.8 Hz, 1 H).

Examples 209-211 listed in Table 8 were prepared following the proceduredescribed for Example 208. TABLE 8

Example R¹ (M + H)⁺ 208 —CH₂N(Me)Bn 387 209 —CH₂N(Me)(CH₂)₂Ph 467 210—CH₂-(4-Bn-piperidin-1-yl) 507 211 CON(Me)(Bn) 466 215 CO₂Me 378

Example 2122-(2-tert-Butylphenoxy)-N-(5-phenyl-1,2,4-thiadiazol-3-yl)pyridine-3-amine

A solution of 2-(2-tert-butylphenoxy)-3-iodopyridine (Example 206a) (145mg, 0.413 mmol) and 5-phenyl-1,2,4-thiadiazol-3-amine (88 mg, 0.50 mmol)(F. Kurzer, J. Chem. Soc., 1956, 4524) in oxygen free toluene (2 ml) wastreated with tris (dibenzylideneacetone)dipalladium (5.2 mg, 0.0056mmol), 1,1-bis(diphenylphosphino)-ferrocene (5.0 mg, 0.009 mmol) andsodium tert-butoxyde (40 mg, 0.42 mmol). The reaction was heated at 120°C. for 16 h, cooled at 23° C., diluted with AcOEt and washed with H₂O.The organic solution was dried (MgSO₄) and concentrated to a crudematerial. Purification by flash chromatography (silica gel, CH₂Cl₂)provided Example 212 (138 mg, 83%). (M+H)⁺=402; ¹H NMR (400 MHz, CDCl₃)δ ppm 1.46 (s, 9 H), 6.97 (dd, J=8.1, 1.5 Hz, 1 H), 7.07 (dd, J=7.9, 5.0Hz, 1 H), 7.20 (dt, J=7.4, 1.5 Hz, 1 H), 7.26 (dd, J=7.8, 2.0 Hz, 1 H),7.48-7.61 (m, 4 H), 7.82 (dd, J=6.6, 1.6 Hz, 1 H), 7.94-8.0 (m, 2 H),8.18 (bs, 1 H), 8.95 (dd,J=8.1, 1.7 Hz, 1 H).

Example 213 N-(2-(2-tert-butylphenoxy)pyridin-3-yl)pyrimidin-4-amine

Example 213 was prepared following the procedure described for Example212.

Example 214N³-(2-(2-tert-Butylphenoxy)pyridin-3-yl)-N⁴-(4-trifluoromethoxy)phenyl)-1,2,5-thiadiazole-5-oxide-3,4-diamine

Example 214aN³-((4-Trifuoromethoxy)phenyl)-1,2,5-thiadiazole-S-oxide-3,4-diamine

A cold (0° C.) solution of 2-(2-tert-butylphenoxy)pyridin-3-amine(Intermediate 1) (354 mg, 2.0 mmol) in CHCl₃ (3 mL) was treated dropwisewith Al(CH₃)₃ (2 M in hexanes, 2.3 mL, 4.6 mmol) and stirred for 3 h. Asolution of 1,2,5-thiadiazole-S-oxide-3,4-diamine (486 mg, 3.0 mmol) inCHCl₃ (6 mL) was added and the mixture was stirred at (0° C.) for 4 h.The mixture was treated with NH₄Cl std solution, diluted with AcOEt,stirred for 1 h and filtered on Celite® pad. The organic phase wasseparated, dried (MgSO₄) and concentrated to a crude material.Purification by flash chromatography (silica, 5 to 10% AcOEt in CH₂Cl₂)provided Example 214a (265 mg, 43%) as a crystalline material, m.p. 186°C.; (M+H)⁺=307; ¹H NMR (400 MHz, CD₃OD) δ ppm 4.26 (s, 3 H), 7.34 (d,J=8.4 Hz, 2 H), 7.95-8.05 (m, 2 H).

Example 214

To a cold (0° C.) solution of 2-(2-tert-butylphenoxy)pyridin-3-amine(Intermediate 1) (48.4 mg, 0.20 mmol) in CH₂Cl₂ (1.5 mL) kept under anargon atmosphere was added dropwise (5 min) Al(CH₃)₃ (2 M in hexanes,0.40 mL, 0.80 mmol). The mixture was stirred for 1.5 h, treated withExample 214a (30.7 mg, 0.10 mmol) and stirred at 23° C. for 2 h. Excessof Al(CH₃)₃ was destroyed by adding NH4Cl std solution. The mixture wasdiluted with CH₂Cl₂ (3 ML) and stirred for 0.25 h. The organic phase wasseparated, dried (MgSO₄) and concentrated to a crude material.Purification by preparative HLPC (YMC-Pack ODS-A 100×20mm I.D. S-5 μm,12 nm, CH₃CN:H₂O:NH₄OAc (5M)=1.3:3.7:0.01 to 9:1:0.01; flow=20 mL/min;grad. time=7 min) provided Example 214 (10 mg, 19%);.(M+H)⁺=517; ¹H NMR(400 MHz, CD₃OD) δ ppm 1.36 (s, 9 H), 7.06 (dd, J=8.1, 1.3 Hz, 1 H),7.18-7.25 (m, 2 H), 7.29 (dt, J=7.5, 1.5 Hz, 1 H), 7.37 (d, J=8.6 Hz, 2H), 7.50 (dd, J=7.9, 1.4 Hz, 2 H), 7.86-7.99 (m, 3 H), 7.94 (dd, J=5.0,1.6 Hz), 8.65 (m, 1 H).

Example 215 Methyl6-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)nicotinate

To a solution of 2-(2-tert-butylphenoxy)pyridin-3-amine (Intermediate 1)(100 mg, 0.413 mmol) and methyl 6-chloronicotinate (355 mg, 2.07 mmol)in oxygen-free THF (2 mL) was added Nolan catalyst (10 mg) followed bysodium tert-butoxyde (39 mg, 0.41mmol). The reaction was stirred atrefluxed for 3 h and partitioned between H₂O and AcOEt. The organicphase was dried (MgSO₄) and concentrated to give crude material.Purification by flash chromatography (silica gel, 15% AcOEt/hexanes theCH₂Cl₂) provided Example 215 (18 mg, 12%). (M+H)⁺=378.1817; ¹H NMR (400MHz, CDCl₃) δ ppm 1.38 (s, 9 H), 3.93 (s, 3 H), 6.75 (d, J=8.0 Hz, 1 H),6.95 (dd, J=7.9, 1.3 Hz, 1 H), 7.05 (dd, J=8.1, 5.0 Hz, 1 H), 7.16 (dt,J=7.8, 1.5 Hz, 1 H), 7.23 (dd, J=7.9, 1.8 Hz, 1 H), 7.43 (bs, 1 H), 7.46(dd, J=7.8, 1.8 Hz, 1 H), 7.81 (dd, J=4.8, 1.8 Hz, 1 H), 8.13 (dd,J=8.6, 2.2 Hz, 1 H), 8.80 (dd, J=7.8, 1.8 Hz, 1 H), 8.93 (d, J=1.8, 1H).

Example 216 N-(2-(2-tert-Butylphenoxy)pyridine-3-yl)pyrazin-2-amine

A solution of 2-(2-tert-butylphenoxy)pyridin-3-amine (342 mg, 1.41 mmol)in dry THF (5 mL) was cooled at 0° C. and treated successively withn-BuLi (1.6M, 0.89 mL, 1.42 mmol) and chloropyrazine (90 mg, 0.79 mmol).After stirring at 23° C. for 24 h, the reaction was diluted with AcOEt.The organic solution was washed with H₂O, dried (MgSO₄) and concentratedto give crude material. Purification by flash chromatography (silica,CH₂Cl₂) provided Example 216 (40 mg, 16%) as a yellow foam. (M+H)⁺=320;¹H NMR (400 MHz, CDCl₃) δ ppm 1.43 (s, 9 H), 7.00 (dd, J=7.8, 1.3 Hz, 1H), 7.04 (dd, J=8.1, 5.0 Hz, 1 H), 7.37 (dt, J=7.3, 1.3 Hz, 1 H), 7.25(dd, J=7.9, 1.8 Hz, 1 H), 7.29 (bs, 1 H), 7.50 (dd, J=8.1, 1.8 Hz, 1H),7.82 (dd, J=5.1, 1.8 Hz, 1 H), 8.11 (bs, 1 H), 8.24 (bs, 1 H), 8.84 (dd,J=8.1, 1.8 Hz, 1 H).

Example 217[2-(2-tert-Butyl-phenoxy)-pyridin-3-yl]-(4-phenyl-thiazol-2-yl)-amine

Example 217a1-Benzoyl-3-[2-(2-tert-butyl-phenoxy)-pyridin-3-yl]-thiourea

A mixture of 2-(2-tert-Butylphenoxy)-3-aminopyridine (200 mg, 0.82 mmol)and benzoyl isothiocyanate (133 μL, 0.99 mmol, 1.2 eq) in DCM (10 mL)was heated at reflux for 1 h. The mixture was cooled to rt andevaporated to give the crude product. Purification by flashchromatography (silica, 0-50% EtOAc/hexane gradient) provided Example217a as a white fluffy powder. (M+H)⁺=406.29.

Example 217b [2-(2-tert-Butyl-phenoxy)-pyridin-3-yl]-thiourea

A mixture of Example 217a (100 mg, 0.24 mmol) and 2 N LiOH solution (240μL, 0.48 mmol, 2 eq) in a 1:1 mixture of MeOH and THF (2 mL) was stirredat 50° C. for 1 h. The solvent was removed. The residue was dissolved inEtOAc (15 mL), washed with water and brine, dried (MgSO₄), filtered andevaporated to give the crude product. Purification by flashchromatography (0-50% EtOAc/hexane) gave Example 217b (62 mg) as a whitesolid. (M+H)⁺=302.25.

Example 217

A mixture of Example 217b (13 mg, 0.043 mmol), 2-bromoacetophenone (9mg, 0.045 mmol) in ethanol (1.5 ml) was heated at 100° C. for 1 h. Thesolvent was removed and residue was purified by flash chromatography (12g ISCO silica column, 0-50% EtOAc/hexane gradient) to give Example 217(10.1 mg) as a white powder. Rf (30% EtOAc/hexane) 0.70; (M+H)⁺=402.35;¹H NMR (400 MHz, CDCl₃) δ ppm 1.41 (s, 9 H), 6.94 (s, 1 H), 6.95 (dd,J=7.91, 1.32 Hz, 1 H), 7.07 (dd, J=7.91, 4.83, 1H), 7.16-7.26 (m, 2 H),7.34 (t, J=7.25 Hz, 1 H), 7.42-7.49 (m, 3 H), 7.73 (s, 1 H), 7.78 (dd,J=5.05, 1.54 Hz, 1H), 7.89-7.92 (m, 2 H), 8.80 (dd, J=7.91, 1.76 Hz, 1H).

Examples 218-250 listed in Table 9 were prepared following the proceduredescribed for Example 217. TABLE 9

Example R^(1a) R^(1b) (M + H)⁺ 217 H Ph 402.4 218 H 4-Me-Ph 416.4 219 H4-OCF₃-Ph 486.3 220 H 4-CN-Ph 427.3 221 H 4-OMe-Ph 432.3 222 H 4-CF₃-Ph470.1 223 H Et 354.3 224 Me Ph 416.4 225 Me Me 354.3 226 H t-Bu 382.3227 CO₂Et Me 412.2 228 CO₂Et H 398.2 229 H 4-NO₂-Ph 447.2 230 H 3-NO₂-Ph447.3 231 H 2-NO₂-Ph 447.2 232 H 3-OMe-Ph 432.4 233 H 2-OMe-Ph 432.3 234H 3-F-Ph 420.4 235 H H 326.4 236 H CO₂Et 398.3 237 CO₂Me t-Bu 440.3 238CO₂Et CF₃ 466.2 239 CN Ph 427.3 240 —CH₂CO₂H Ph 460.3 241 —CH₂CO₂Et Ph488.3 242 H —C(Me)₂CH₂CO₂Et 454.3 243 H

511.3 244 H —CH₂CO₂(i-Pr) 426.3 245 H CF₂CF₃ 444.3 246 H CF₃ 394.3 247 H2-CO₂Et-Ph 474.3 248 Ph H 402.4 249 —CH₂OMe H 370.3 250 H

411.3 251 —CH₂OH H 356.3 252 —CH₂OH t-Bu 412.3 253 —CH₂OH CF₃ 424.2 254CON(Me)(Bn) H 473.3 255 CONMe₂ H 397.3 256 —CO-morpholin-4-yl H 439.2257 CONHPh H 445.3 258 CONH-neopentyl H 439.3 259 CON(Me)Pr H 425.3 260CONHPr H 411.3 261 CON(Me)Et H 411.3 262 CONH(t-Bu) H 425.3 263CON(Me)-phenethyl H 487.3 264 CON(Me)(CH₂)₃Ph H 501.3 265CON(Me)(CH₂-pyridin-3-yl) H 474.3 266 CON(Me)Et CF₃ 479.3 267 CON(Me)BnCF₃ 541.2 268 CONHPh CF₃ 513.2 269 CONH₂ CF₃ 437.4 270 —CH₂CON(Me)Et Ph501.3 271 —CH₂CONHBn Ph 549.3 272 —CH₂N(Me)Bn H 359.3 273—CH₂NH-neopentyl H 425.0 274 —CH₂NHBn H 445.3 275 —CH₂N(Me)Et H 397.3276 —CH₂N(Me)(t-Bu) H 425.3 277 —CH₂N(Me)-cyclohexyl H 451.3 278—CH₂N(Me)-phenethyl H 473.3 279 —CH₂N(Me)(CH₂)₃Ph H 487.3 280

H 473.3 281 —CH₂N(t-Bu)Bn H 501.3 282 —CH₂N(i-Pr)Bn H 487.3 283—CH₂N(Me)-pyridin-3-yl H 460.3 284 —CH₂N(Me)Et t-Bu 453.4 285 —CH₂NHEtt-Bu 439.3 286 —CH₂N(Me)Bn t-Bu 515.3 287 —CH₂NHBn t-Bu 501.3 288—CH₂N(Me)-phenethyl t-Bu 529.3 289 —CH₂N(t-Bu)Bn t-Bu ND 290—CH₂N(i-Pr)Bn t-Bu ND 291 —CH₂N(Me)(CH₂)₃Ph t-Bu ND 292—CH₂-isoindolin-2-yl H 457.3 293 —CH₂-(1,2,3,4-tetrahydro- H 471.3isoquinolin-2-yl) 294

H 473.3 295 —CH₂N(Me)Ph H 445.3 296 —CH₂-isoindolin-2-yl t-Bu 513.3 297—CH₂-(1,2,3,4-tetrahydro- t-Bu 527.3 isoquinolin-2-yl) 298

t-Bu 529.3 299 —CH₂N(Me)Ph t-Bu ND 300 —CH₂N(Me)Et t-Bu 467.3 301—CH₂-morpholin-4-yl t-Bu 481.3 302 —CH₂N(Me)Et CF₃ 465.3 303 —CH₂N(Me)BnCF₃ 527.2 304 —CH₂-isomdolin-2-yl CF₃ 525.2 305 —CH₂NHEt CF₃ 451.3 306 HCONHPr 411.3 307 H CON(Me)Pr 425.3 308 H CONHBn 459.2 309 H CON(Me)Bn473.3 310 H CONHPh 445.2 311 H CONH(t-Bu) 425.3 312 H CON(Me)Bn 313 HCONH-neopentyl 439.3 314 H CON(Me)(t-Bu) 439.3 323 4-CF₃-Ph CF₃ 538.3324 3-Me-Ph CF₃ 484.3 325 4-Me-Ph CF₃ 484.3 326 2-Me-Ph CF₃ 484.3 3273-CN-Ph CF₃ 495.3 328 pyridin-4-yl CF₃ 471.3 329 3-OMe-Ph CF₃ 500.3 3304-OMe-Ph CF₃ 484.3 331 4-SO₂Me-Ph CF₃ 548.2 332 4-CH₂OH-Ph CF₃ 500.3 3333-OH-Ph CF₃ 486.3 334 Br CF₂CF₃ 522.2 335 Ph CF₃ 370.3 336 4-CN-Ph CF₃495.3 337 3,5-diF-Ph CF₃ 506.3 338 2-CN-Ph CF₃ 495.3 339 2,4-diF-Ph CF₃506.3 340 4-CO₂Me-Ph CF₃ 528.3 341 3-CO₂Me-Ph CF₃ 528.3 342 3-OCF₃-PhCF₃ 554.3 343 Ph CF₂CF₃ 520.3 344 4-Me-Ph CF₂CF₃ 534.3 345 3-CF₃-Ph CF₃538.3 346 4-OCF₃-Ph CF₃ 554.2 347 3-CF₃-Ph CF₂CF₃ 588.2 348 4-OCF₃-PhCF₂CF₃ 604.2 349 3-Me-Ph CF₂CF₃ 545.3 350 3-CN-Ph CF₂CF₃ 545.3 3514-CN-Ph CF₂CF₃ 545.3 352 3-OMe-Ph CF₂CF₃ 550.3 353 4-OMe-Ph CF₂CF₃ 550.3354 furan-3-yl CF₃ 460.3 355 4-OBn-Ph CF₃ 576.3 356 3-F-4-OMe-Ph CF₃518.3 357 3,4,5-triOMe-Ph CF₃ 560.3 358 1,3-benzodioxol-4-yl CF₃ 514.3359 3-OBn-Ph CF₃ 576.3 360 2-OMe-pyrimidin-5-yl CF₃ 619.3 361morpholin-4-yl CF₃ 406.3 362 piperidin-1-yl CF₃ 477.3 363—N(Me)—CH₂-pyridin-4-yl CF₃ 514.3 364 —N(Me)—CH₂-pyridin-3-yl CF₃ 514.3365 —N(Me)(1-Me-piperidin-4-yl) CF₃ 520.3 366 pyrrolidin-1-yl CF₃ 463.3367 4-Et-piperazin-1-yl CF₃ 506.3 368 piperazin-1-yl CF₃ 478.3 3694-Me-piperazin-1-yl CF₃ 492.3 370 4-(pyrrolidin-1-yl)-piperidin-1- CF₃546.3 yl 371 4-Bn-piperazin-1-yl CF₃ 568.3 372 4-1-Pr-piperazin-1-yl CF₃520.3 373

CF₃ 518.3 374 3-(-CH₂NMe₂)-Ph CF₃ 527.3 375 3-(-CH₂N(Me)Bn)-Ph CF₃ 603.3376 3-(-CH₂NHBn)-Ph CF₃ 589.3 377 3-(-CH₂NHMe)-Ph CF₃ 513.3 3784-(-CH₂NMe₂)-Ph CF₃ 527.3 379 4-(-CH₂NHMe)-Ph CF₃ 513.3 3804-(-CH₂N(Me)Bn)-Ph CF₃ 603.3 381 4-(-CH₂NHBn)-Ph CF₃ 589.3 3822-(-CH₂NMe₂)-Ph CF₃ 527.3 383 2-(-CH₂NHMe)-Ph CF₃ 513.3 3842-(-CH₂N(Me)Bn)-Ph CF₃ 603.3 385 2-(-CH₂NHBn)-Ph CF₃ 589.3 3863-(-CH₂NHMe)-4-OMe-Ph CF₃ 543.3 387 2-(-CH₂NMe₂)-4-OMe-Ph CF₃ 557.3 3882-(-CH₂NHBn)-4-OMe-Ph CF₃ 619.3 389 2-(-CH₂N(Me)Bn)-4-OMe-Ph CF₃ 633.3390 H —C(Me)₂CH₂CON(Me)Et 467.4 391 H —C(Me)₂CH₂CONHBn 515.3 392 H—C(Me)₂CH₂CON(Me)Bn 529.3 393 H —C(Me)₂CH₂CO- 495.3 morpholi-4-yl 394 H2-(-CH₂N(Me)Et)-Ph 473.4 395 H 3-CH₂OH-Ph 432.4 396 H 4-CH₂OH-Ph 432.4397 —(CH₂)₂OH Ph 446.3 398 H 2-(-CH₂NHEt)-Ph 459.4 399 H 2-(-CH₂NHBn)-Ph521.4 400 H 2-(-CH₂N(Me)Bn)-Ph 535.4 401 H 3-(-CH₂NMe₂)-Ph 459.4 402 H3-(-CH₂N(Me)Bn)-Ph 535.3 403 H 4-(-CH₂N(Me)Bn)-Ph 535.3 404 CN CF₃ 419.3405 CN H 406 H CN 407 1H-tetrazol-5-yl H 394.3 432 1H-1,2,4-triazol-3-ylCF₃ 461.3 433 CN CF₃ 407.3 434 CN t-Bu 407.3 435 CO₂Et Ph 474.3 441—SO₂N(Me)Bn Me 523.3 442 —SO₂N(Bn)₂ Me 599.3 443 —SO₂N(Me)Et Me 461.3444 —SO₂NHBn Me 509.3 445 —SO₂-morpholin-4-yl Me 489.3 446 —SO₂NHEt Me447.3

Example 251(2-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)thiazol-5-yl)methanol

Example 251a2-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)thiazole-5-carboxylic acid

A mixture of Example 228 (1.63 g, 4.1 mmol), 1 N NaOH solution (16.4 mL,16.4 mmol) in MeOH) 50 mL was heated at reflux for 6 h. The solvent wasremoved and the residue was acidified to pH=2-3. The solid was collectedby filtration, washed with water and dried to give Example 251a (1.30 g)as a white powder. (M+H)⁺=370.2.

Example 251

To a solution of Example 251a (200 mg, 0.54 mmol) in THF (2 mL) at rtwas added borane-THF complex (1.0 M, 1.1 mL, 1.1 mmol). The mixture wasstirred at rt overnight. LC-MS showed no completion. Another 1.1 mL ofborane-THF solution was added and stirred at rt for additional 6 h. Thereaction was quenched with water (5 mL) and extracted with EtOAc (2×15mL). The combined organic layers were washed with saturated sodiumbicarbonate solution and brine, dried over magnesium sulfate, filteredand evaporated to give the crude product. Purification by flashchromatography (12 g ISCO column, 0-50% EtOAc/hexane) gave Example 251(20 mg) as a colorless film. (M+H)⁺=356.3.

Example 252(4-tert-Butyl-2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)thiazol-5-yl)methanol

Example 252 was prepared from Example 237 according to a similarprocedure described for Example 251 as a white foam. (M+H)⁺=412.3

Example 253(2-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-4-(trifluoromethyl)thiazol-5-yl)methanol

Example 253 was prepared from Example 238 according to a similarprocedure described for Example 251 as a white foam. (M+H)⁺=424.2

Example 254N-Benzyl-2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-N-methylthiazole-5-carboxamide

A mixture of compound2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)thiazole-5-carboxylic acid(Example 251a, 30 mg, 0.081 mmol), N-benzylmethylamine (13 μL, 0.097mmol), EDC (18 mg, 0.097 mmol) and HOBt (2 mg, 0.016 mmol) in DCM (1 mL)was stirred at rt overnight. The mixture was evaporated and purified byreverse phase prep HPLC to give Example 254 (15 mg) as a white foam.(M+H)⁺=473.25.

Examples 255-271 listed in Table 9 were prepared following the proceduredescribed for Example 254.

Example 272N-(5-((Benzyl(methyl)amino)methyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

Example 272a2-(2-tert-Butylphenoxy)-N-(5-(chloromethyl)thiazol-2-yl)pyridin-3-amine

To a solution of(2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-thiazol-5-yl)methanol(Example 251, 55 mg, 0.15 mmol) in DCM (3 mL) was added thionyl chloride(45 μL, 0.60 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h.The mixture was evaporated to give Example 272a (65 mg) as a whitesolid.

Example 272

A mixture of Example 272a (30 mg, 0.080 mmol) and N-benzylmethylamine(13 μL, 0.097 mmol) in THF (2 mL) was stirred at rt overnight. Themixture was evaporated and purified by reverse phase prep HPLC to giveExample 272 (21 mg) as a colorless film). (M+H)⁺=359.31.

Examples 273-305 listed in Table 9 were prepared following the proceduredescribed for Example 272.

Examples 306-313 listed in Table 9 were prepared following a similarprocedure from ethyl2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)thiazole-4-carboxylate(Example 236) described for Example 254.

Example 3155-Benzyl-N-(2-(2-tert-butylphenoxy)pyridin-3-yl)-4,5,6,7-tetrahydrothiazolo-5,4-c]pyridin-2-amine

Example 315a Benzyl 3-bromo4-oxocyclohexanecarboxylate

To a solution of benzyl 4-oxo-1-piperidine-carboxylate (1.0 g, 4.28mmol) in diethyl ether (20 mL) at rt was added bromine dropwise. Theresulting mixture was stirred at rt for 1 h. The mixture was dilutedwith EtOAc (30 mL), washed with water and brine, dried over MgSO₄ andfiltered. The filtrate was evaporated to give the crude product whichwas purified by flash chromatography (40 g ISCO column, 0-30%EtOAc/hexane gradient) provided Example 315a (800 mg) as a colorlessoil.

Example 315b Benzyl2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-6,7-dihydrothiazolo-[5,4-c]pyridine-5(4H)-carboxylate

A mixture of 1-(2-(2-tert-butylphenoxy)pyridin-3-yl)thiourea (Example217b) (100 mg, 0.33 mmol) and Example 315a in ethanol was heated at 95°C. for 2 h. The solvent was removed and the residue was purified byflash chromatography (12 g ISCO column, 0-20% EtOAc/hexane gradient)provided Example 315b (64 mg) as a colorless film. (M+H)⁺=515.3.

Example 315cN-(2-(2-tert-Butylphenoxy)pyridin-3-yl)-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-amine

Example 315b (550 mg, 1.07 mmol) was treated with 30% HBr solution at rtfor 30 min to give a clear orange solution. The mixture was diluted withdiethyl ether (100 mL). The solid was collected by filtration and washedwith ether to give Example 315c (440 mg). (M+H)⁺=381.3.

Example 315

A mixture of Example 315c (32 mg, 0.084 mmol), benzyl bromide (12 μL,0.10 mmol), DIPEA (44 μL, 0.25 mmol) in DCM (2 mL) was stirred at rtovernight. The mixture was evaporated and the residue was purified byreverse phase preparative HPLC to give Example 315 (10 mg, TFA salt) asa white foam. (M+H)⁺=471.3.

Examples 316-317 listed in Table 10 were prepared following theprocedure described for Example 315. Examples 318-322 listed in Table 10were prepared by treating Example 315c with corresponding carbonylchlorides or sulfonyl chlorides and DIPEA in DCM. TABLE 10

Example

(M + H)⁺ 315

471.3 316

201.0 317

289.2 318

1426.29 319

1652.39 320

1072.18 321

150.08 322

297.62 436

422.3 438

470.3

Example 3232-(2-tert-Butylphenoxy)-N-(4-(trifluoromethyl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)pyridin-3-amine

Example 323aN-(5-Bromo-4-(trifuoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

To a solution of2-(2-tert-butylphenoxy)-N-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine(Example 246) (1.05 g, 2.67 mmol) in AcOH/THF (1:1, 30 mL) at rt wasadded NBS (475 mg, 2.67 mmol) portionwise. The resulting mixture wasstirred at rt for 2 h. The mixture was diluted with EtOAc (200 mL),washed with 1 N NaOH, water and brine, dried over magnesium sulfate,filtered and evaporated to give the crude product. Purification by flashchromatography (40 g ISCO column, 0-20% EtOAc hexane gradient) providedExample 323a (1.08 g). (M+H)⁺=472.3.

Example 323

To a solution of Example 323a (32 mg, 0.068 mmol) in toluene/methanol(2:1, 400 μL) was added 4-(trifluoromethyl)phenyl boronic acid (26 mg,0.14 mmol), 2 M Na₂CO₄ solution (136 mL, 0.27 mmol). The mixture wasbubbled with nitrogen, added catalyst Pd(PPh₃)₄ (7 mg) and heated at 85°C. overnight. The mixture was diluted with EtOAc, washed with brine,dried over magnesium sulfate, filtered and evaporated to give the crudeproduct. Purification by reverse phase preparative HPLC provided Example323.(19 mg). (M+H)⁺=538.3.

Examples 324-360 listed in Table 9 were prepared following a similarprocedure described for example 323.

Example 3612-(2-tert-Butylphenoxy)-N-(5-morpholino4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

A mixture ofN-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)-pyridin-3-amine(Example 323a) (20 mg, 0.042 mmol) and morpholine (200 μL) was heated at100° C. overnight. The reaction was concentrated and the residue waspurified by reverse phase preparative HPLC to give Example 361 (12 mg)as a white foam. (M+H)⁺=406.29.

Examples 362-373 listed in Table 9 were prepared following the proceduredescribed for Example 361.

Example 3742-(2-tert-Butylphenoxy)-N-(5-(3-((dimethylamino)methyl)phenyl)-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example 374a3-(2-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-4-(trifluoromethyl)thiazol-5-yl)benzaldehyde

Example 374a was synthesized fromN-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine(Example 323a) and 3-formylphenyl boronic acid according to a similarprocedure described for Example 107. Example 374a was obtained as awhite foam. (M+H)⁺=498.3.

Example 374

To a solution of Example 374a (30 mg, 0.060 mmol) in MeOH (1.0 mL) wasadded (2.0 M in THF, 1.0 mL), HOAc (10 μL, 0.18 mmol), ZnCl₂ (8 mg, 0.12mmol) and NaBH₃CN (8 mg, 0.13 mmol). The mixture was stirred at rtovernight. The reaction was concentrated and the residue was purified byreverse phase preparative HPLC to give Example 361 (25 mg) as acolorless film. (M+H)⁺527.3.

Examples 375-389 listed in Table 9 were prepared according a similarprocedure described for Example 374.

Example 3903-(2-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)thiazol-4-yl)-N-ethyl-N,3-dimethylbutanamide

Example 390a3-(2-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)thiazol-4-yl)-3-methylbutanoicacid

A mixture of Example 242 (420 mg, 0.92 mmol) and 1 N NaOH solution (5mL) in THF/MeOH (1:3) was stirred at 70° C. for 4 h. The reaction wascooled to rt, acidified to pH=2˜3, extracted with EtOAc (3×30 mL). Theorganic layers were combined and evaporated to give the crude product.Purification by flash chromatography (12 g ISCO column, 0-100%EtOAc/hexane) give the title product (170 mg). (M+H)⁺=426.4.

Example 390

A mixture of Example 390a (25 mg, 0.059 mmol), N-ethyl methyl amine (50μL, 0.59 mmol), EDC (17 mg, 0.088 mmol) and HOBt (2 mg) was stirred atrt overnight. The reaction was evaporated and purified by reversepreparative HPLC to give Example 390 (5 mg) as a white solid.(M+H)⁺=467.4.

Examples 391-393 listed in Table 9 were prepared according a similarprocedure described for Example 390.

Example 3942-(2-tert-Butylphenoxy)-N-(4-(2-((ethyl(methyl)amino)methyl)phenyl)thiazol-2-yl)pyridin-3-amine

Example 394a(2-(2-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)thiazol-4-yl)phenyl)methanol

To a solution of ethyl2-(2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)thiazol-4-yl)benzoate(Example 247, 210 mg, 0.44 mmol) in THF (3.0 mL) at rt was addedSuper-Hydride ((1.0 M/THF, 2.2 mL, 2.2 mmol). The reaction was stirredat rt overnight, quenched with the addition of water and extracted withEtOAc. The combined organic layers were dried (MgSO₄), filtered andevaporated to give the crude product. Purification by flashchromatography (12 g ISCO column, 0-50% EtOAc/hexane) provided Example394a (137 mg) as a white foam. (M+H)⁺=432.3.

Example 394bN-(4-(2-(Bromomethyl)phenyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

To a solution of Example 394a (124 mg, 0.29 mmol) in DCM (3 mL) wasadded a solution of PBr₃ (1.0 M/DCM). The mixture was stirred at rt for1 h. The reaction was poured over ice/water (10 mL) and the mixture wasextracted with EtOAc (3×15 mL). The combined organic layers were washedwith saturated NaHCO₃ solution, brine, dried (MgSO₄), filtered andevaporated to give Example 394b (129 mg) as a white foam. (M+H)⁺=495.2.

Example 394

A mixture of Example 394b (20 mg, 0.04 mmol), N-ethyl methylamine (20μL) in THF was stirred at rt overnight. The reaction was evaporated andthe residue was purified by reverse preparative HPLC to give Example 394(8 mg) as a white solid. (M+H)⁺=473.4.

Example 395-403 listed in Table 9 was prepared according to a similarprocedure described for Example 394.

Example 4042-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-4-(trifluoromethyl)thiazole-5-carbonitrile

To a solution of2-(2-(2-tert-butylphenoxy)-pyridin-3-ylamino)-4-(trifluoromethyl)-thiazole-5-carboxamide(Example 269, 89 mg, 0.20 mmol) in THF (1 mL) at 0° C. was addedpyridine (99 μL, 1.2 mmol) followed by the addition of TFAA (113 μL, 0.8mmol). The mixture was stirred at rt for 1 h. The mixture was dilutedwith EtOAc (20 mL), washed with 1 N HCl (10 mL) and brine (10 mL), dried(MgSO₄), filtered and evaporated to give to give the crude product.Purification by flash chromatography (12 g ISCO column, 0-30%EtOAc/hexane) provided Example 404 (137 mg) as a white solid.(M+H)⁺=419.3.

Examples 405-406 listed in Table 9 was prepared according to a similarprocedure described for Example 404.

Example 407N-(5-(1H-Tetrazol-5-yl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

A mixture of2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-4-(trifluoromethyl)thiazole-5-carbonitrile(Example 404, 40 mg, 0.114 mmol), ammonium chloride (6.4 mg, 0.12 mmol),sodium azide (8 mg, 0.12 mmol) in DMF (200 μL) was heated at 90-95° C.overnight. The mixture was quenched with ice-water, acidified to pH=2using 1 N HCl solution, extracted with DCM (3×15 mL). The combinedorganic layers were dried (MgSO₄), filtered and evaporated to give togive the crude product. Purification by flash chromatography (12 g ISCOcolumn, 0-10% EtOAc/hexane) provided Example 407 (25 mg) as a whitesolid. (M+H)⁺=394.3.

Example 4084-tert-Butyl-N-(2-(2-tert-butylphenoxy)phenyl)thiazol-2-amine

Example 408a 1-(2-(2-tert-Butylphenoxy)phenyl)thiourea

Example 408a was prepared from compound Intermediate 4 following asimilar procedure described for[2-(2-tert-Butyl-phenoxy)-pyridin-3-yl]-thiourea (Example 217b).

Example 408

Example 408 was prepared from Example 408a following a similar proceduredescribed for Example 217.

Examples 409-419 listed in Table 11 were prepared following a similarprocedure described for Example 408. TABLE 11

Example R^(1a) R^(1b) (M + H)⁺ 408 H t-Bu 409 H Ph 401.3 410 H Et 411 MePh 415.3 412 H H 325.3 413 CO₂Et Me 411.3 414 CO₂H H 369.3 415 CO₂Et H397.2 416 H Me 339.8 417 H CO₂Et 397.3 418 CONHMe H 382.3 419 CONMe₂ H396.3

Example 4202-(2-tert-Butyl-phenoxy)-pyridin-3-yl]-(5-phenyl-oxazol-2-yl)-amine

Example 420a 2-Azido-1-phenyl-ethanone

Sodium azide (68 mg, 1.05 mmol) was added to a solution of 2-henone (200mg, 1.0 mmol) in a 3:1 mixture of acetone and water (12 mL). The mixturewas stirred at rt overnight. The solvent was removed and the residue wasdiluted with EtOAc (20 mL) and washed with brine. The organic layer wasdried (MgSO₄), filtered and evaporated to give the crude product.Purification by flash chromatography (silica, 0-20% EtOAc/hexanegradient) provided Example 420a (118 mg) as a colorless oil. Rf (20%EtOAc/hexane) 0.42. (M+H)⁺=162.10.

Example 420

A mixture of Example 420a (108 mg, 0.67 mmol),2-(2-tert-butyl-phenoxy)-3-isothiocyanato-pyridine (Example 1c, 160 mg,0.56 mmol) and triphenyl phosphine resin bound (1.6 mmol/g resin, 525mg, 0.84 mmol) in dioxane (5 mL) was heated at 90° C. for 4 h. Themixture was filtered and evaporated. The residue was purified by flashchromatography (12 g ISCO silica column, 10-30% EtOAc/hexane gradient)to give Example 420 (139 mg) as an orange solid. (M+H)⁺=386.33; ¹H NMR(400 MHz, CDCl₃) δ ppm 1.48 (s, 9 H), 7.00 (dd, J=7.91, 1.32 Hz, 1H),7.10 (dd, J=7.91, 4.83 Hz, 1H), 7.21-7.35 (m, 4 H), 7.45 (t, J=7.69 Hz,2 H), 7.61 (dd, J=8.57, 1.10 Hz, 2 H), 7.70 (s, 1 H), 7.84 (dd, J=4.83,1.76 Hz, 1H), 8.80 (dd, J=7.91, 1.76 Hz, 1 H), 8.70 (dd, J=8.13, 1.54Hz, 1 H).

Examples 421-422 listed in Table 12 were prepared according a similarprocedure described for Example 420. TABLE 12

Example R^(1a) R^(1b) (M + H)⁺ 420 Ph H 386.3 421 4-Me-Ph H 400.3 4224-OCF₃-Ph H 470.3 437 CO₂Et CF₃ 450.3 439 CO₂Et Me 396.3 440 CO₂Et H382.3

Example 4232-(2-tert-Butylphenoxy)-N-(5-o-tolyl4H-1,2,4-triazol-3-yl)pyridin-3-amine

Example 423a1-(2-(2-tert-Butylphenoxy)pyridin-3-yl)-3-(2-methylbenzoyl)thiourea

A mixture of 2-(2-tert-Butylphenoxy)-3-aminopyridine (Intermediate 1)(50 mg, 0.20 mmol) and 2-methylbenzoyl isothiocyanate (36 μL, 0.24 mmol,1.2 eq) in DCM (10 mL) was heated at reflux for 1 h. The mixture wascooled to rt and evaporated to give the crude product. Purification byflash chromatography (silica, 0-20% EtOAc/hexane gradient) providedExample 423a (91 mg) as white crystals. (M+H)⁺=420.25.

Example 423

A mixture of Example 423a (50 mg, 0.12 mmol), hydrazine monohydrate (29μL, 0.6 mmol, 5.0 eq) in 2:1 MeOH:THF (3 mL) was heated at 60° C.overnight. The solvent was removed and the residue was purified byreveres phase preparative HPLC to give Example 423 (139 mg) as a lightyellow powder. (M+H)⁺=400.36; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.32 (s, 9H), 2.46 (s, 3H), 6.86-6.89 (m, 1H, 7.00 (dd, J=7.69, 5.05 Hz, 1H),7.08-7.15 (m, 2H), 7.23-7.30 (m, 2 H), 7.37-7.41 (m, 2H), 7.48 (d,J=7.48 Hz, 1 H), 7.76-7.78 (m, 1 H), 8.32 (dd, J=7.91, 1.76Hz, ¹H),11.11 (s, broad, 2H).

Examples 424-427 listed in Table 13 were prepared according a similarprocedure described for Example 423. TABLE 13

Example R^(1c) (M + H)⁺ 423 2-Me-Ph 400.4 424 Ph 425 3-Me-Ph 426 4-Me-Ph427 2-Cl-Ph

Example 4282-(2-tert-Butylphenoxy)-N-(4-methyl-5-phenyl-1H-imidazol-2-yl)pyridin-3-amine

Example 428a1,2-Bis-tert-butoxycarbonyl-3-(2-(2-tert-butylphenoxy)pyridin-3-yl)guanidine

To a mixture of 2-(2-tert-Butylphenoxy)-3-aminopyridine (Intermediate 1)(500 mg, 2.06 mmol) and 1,3-bis-boc-2-methyl-2-thiopseudourea (658 mg,2.26 mmol, 1.1 eq) in DMF (30 mL) was added triethylamine (1.1 mL, 8.24mmol, 4.0 eq) and HgCl₂ (643 mg, 2.36 mmol, 1.15 eq). The resultingmixture was stirred at rt for 4 h. The reaction was diluted with EtOAc(150 mL) and filtered through a Celite® cake. The filtrate was washedwith water. The aqueous layer was extracted with EtOAc (2×20 mL). Thecombined organic layers were filtered through Celite® again. Thefiltrate was washed with brine, dried (MgSO₄), filtered and concentratedto give Example 428a (600 mg) as a white foam. (M+H)⁺=485.40.

Example 428b 1-(2-(2-tert-Butylphenoxy)pyridin-3-yl)guanidine

A mixture of Example 428a (560 mg, 1.15 mmol) and 50% TFA/DCM (10 mL)was stirred at rt for 2 h. The reaction was concentrated and the residuewas evaporated with toluene to give the TFA salt of Example 428b as awhite foam (550 mg). (M+H)⁺=285.39.

Example 428

A mixture of Example 428b (30 mg, 0.11 mmol), 2-bromopropiophenone (26mg, 0.12 mmol) and triethylamine (30 μL) in ethanol (1.0 mL) was heatedat 60° C. overnight. The solvent was removed and the residue waspurified by reveres phase preparative HPLC to give Example 428 (16 mg)as a white solic. (M+H)⁺=399.38; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.25 (s,9 H), 2.15 (s, 3H), 7.10 (d, J=7.91 Hz, 1H), 7.15-7.18 (m, 1H),7.22-7.26 (m, 1 H), 7.38-7.45 (m, 4H), 7.48-7.53 (m, 5 H), 8.17 (dd,J=7.91, 1.76 Hz, 1H), 8.36 (dd, J=4.83, 1.76 Hz, 1H).

Examples 429-431 listed in Table 14 were prepared according to a similarprocedure described for Example 428. TABLE 14

Example R^(1a) R^(1b) (M + H)⁺ 428 Ph Me 399.4 429 Ph H 385.4 4304-OCF₃-Ph H 469.3 431 Et H

Example 432N-(5-(1H-1,2,4-Triazol-3-yl)-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

A solution of2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-4-(trifluoromethyl)thiazole-5-carboxamide(Example 269, 33 mg, 0.075 mmol) in N,N-dimethylformamide dimethylacetal (0.5 mL) was stirred at rt for 1 h. The solvent was removed andthe residue was dissolved in HOAc (1 mL) followed by the addition ofhydrazine monohydrate (7 μL). The mixture was heated at 70° C. for 1 h.The reaction was concentrated and the residue was dissolved in EtOAc (10mL), washed with saturated sodium bicarbonate solution (2×5 mL), driedover magnesium sulfate, filtered and evaporated to give the crudeproduct. Purification by reverse phase preparative HPLC provided Example432a (16 mg) as a white solid. (M+H)⁺=461.3.

Example 4332-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-4-(trifluoromethyl)thiazole-5-carbonitrile

Example 433a 2-(2-tert-Butylphenoxy)-3-iodopyridine

To a solution of 2-(2-tert-butylphenoxy)-3-aminopyridine (3.30 g, 13.6mmol) in conc. HCl:water (3:4, 70 mL) at 0° C. was added NaNO₂ (1.04 g,15.0 mmol). Gas evolution is immediately observed. The reaction wasstirred at 0° C. for ˜25 min. and then the reaction was slowly pouredinto a rt solution of KI (6.8, 40.8 mmol) in water (150 ml) to produce adark liquid containing an amount of a black. After heating the reactionat 60° C. for 2 h, the reaction was cooled to rt and extracted withethyl acetate (2×200 mL). The combined ethyl acetate extracts were thenwashed with saturated aqueous Na₂SO₃ (2×300 mL) and saturated aqueousNa₂CO₃ (1×300 mL). The ethyl acetate extracts were then dried overMgSO₄, filtered and concentrated. Purification of the residue by flashchromatography—(110 g ISCO silica gel column, 0 to 5% EtOAc in hexanestep gradient)—gave Example 433a (3.35 g) as a pale yellow solid. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.39 (s, 9H); 6.74 (dd, J=7.47, 4.83 Hz, 1H);6.93 (dd, J=7.91, 1.32 Hz, 1H); 7.12-7.25 (m, 2H); 7.45 (dd, J=7.91,1.76 Hz, 1 H); 8.10 (dd, J=-4.83, 1.76 Hz, 1H); 8.15 (dd, J=7.69, 1.54Hz, 1H).

Example 433b 2-(2-tert-Butylphenoxy)-pyridine-3-boronic acid

To a solution of Example 433a (3.35 g, 9.49 mmol) in THF (60 ml) undernitrogen at −78° C. was added 2.0 M nBuLi in pentane (14.2 mL, 28.47mmol, 3 eq) over ˜3 min. The reaction was stirred at −78° C. for 10 min& then B(OiPr)₃ (6.54 mL, 28.47 mmol, 3 eq) was added in a singlealiquot. The reaction was stirred at −78° C. for 40 min. & then thereaction was poured into water (˜60 mL) followed by the addition of LiOH(˜3.5 g). The reaction was stirred for 2 hr at rt. Partition thereaction mixture between water (˜200 ml additional) and EtOAc (˜200 mL).Separate layers and wash the aqueous once more with EtOAc. Pour aqueousinto a large erlenmyer flask & add EtOAc (˜200 mL). With vigorousstirring add conc. HCl dropwise until pH˜2. Separate layers in sep.funnel & extract aqueous once more with EtOAc (˜200 mL). Combine theselast two EtOAc extracts, dry over sodium sulfate, filter andconcentrate. Azeotrope twice with toluene to give Example 433b (2.38 g)as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.31 (s, 9H); 4.1 (bs,1H); 5.61 (bs, 1H); 6.91 (d, J=7.47 Hz, 1H); 7.05 (dd, J=6.37, 3.74 Hz,1 H); 7.15-7.3 (m, 2H); 7.48 (dd, J=7.47, 1.32 Hz, 1H); 8.23 (bs, 1H);8.27 (dd, J=7.03 Hz, 1H).

Example 433

To a solution of Example 433b (48 mg, 0.177 mmol) in dichloromethane(2.5 mL) in a scintillation vial under air at rt was added2-amino-4-(trifluoromethyl)thiazole-5-carbonitrile (52 mg, 0.27 mmol),powdered 4A molecular sieves (˜100 mg), Et₃N (50 μL), pyridine (50 μL)and lastly Cu(OAc)₂ (35 mg, 0.19 mmol). The reaction vessel was cappedand the reaction was stirred at rt overnight. The reaction mixture wasdiluted with hexane (2.5 mL), loaded to a silica gel column and purifiedby flash chromatography (0-10% EtOAc in hexane, step gradient) toprovide Example 433 (30 mg) as a tan solid. (M+H)⁺=407.3.

Examples 434-440 listed in Table 15 were prepared following theprocedures described for Example 433 using the amines shown in thetable. TABLE 15 Example Amine Structure (M + H)⁺ 434

407.3 435

474.3 436

422.3 437

450.3 438

470.3 439

396.3 440

382.3

Example 4412-[2-(2-tert-Butylphenoxy)-pyridin-3-ylamino]-4-methyl-thiazole-5-sulfonicacid benzyl-methyl-amide

Example 441aN-[5-(Benzyl-methyl-sulfamoyl)-4-methyl-thiazol-2-yl]-acetamide

To a solution of 2-acetamido-4-methylthiazole-5-sulfonylchloride (440mg, 1.73 mmol) in dichloroethane (5 mL) at rt was addedN-methylbenzylamine (418 mg, 3.46 mmol) and iPr₂Net (400 μL). Reactionset at rt for 48 h. After solvent was reduced under vacuum, the residuewas diluted with EtOAc (˜30 mL) and washed twice with 1N HCl and oncewith saturated aqueous NaHCO₃. The EtOAc extract was dried over MgSO₄,filtered and concentrated. The residue was then diluted withdichloromethane and hexane was added to initiate crystallization. Thesolid was collected by filtration to give Example 441a (432 mg) as awhite solid. (M+H)⁺=340.3.

Example 441b 2-Amino4-methyl-thiazole-5-sulfonic acidbenzyl-methyl-amide

Example 441a (432 mg, 1.27 mmol) was diluted with a solution of conc.HCl:water:EtOH (15:20:15 by volume, 5 mL). The reaction mixture washeated at 65° C. for 18 h. The reaction was partitioned between EtOAc(25 mL) and 1:1 sat. NaHCO3:1N NaOH (25 mL). Extract the aqueous layertwice with EtOAc. Dry the combined organic extracts over MgSO₄, filterand concentrate to provide Example 441b (335 mg) as a white solid.(M+H)⁺=298.3.

Example 441

To a solution of Example 433b (25 mg, 0.092 mmol) in dichloromethane(2.5 mL) in a scintillation vial under air at rt was added the productfrom Example 441b (30 mg, 0.101 mmol), powdered 4 Å molecular sieves(˜100 mg), Et₃N (30 μL), pyridine (30 μL) and lastly Cu(OAc)₂ (20 mg,0.11 mmol). The reaction vessel was capped and the reaction was stirredat rt overnight. The reaction mixture was diluted with hexane (2.5 mL)and filtered through a pad of silica gel eluting with 50% EtOAc indichloromethane. After removing the solvent under vaccuum, purificationby preparative TLC (silica gel, 20×20 cm²×1000 μm thick, 20% EtOAc inhexane) gave Example 441 as a white solid. (M+H)⁺=523.3.

Examples 442-446 listed in Table 9 were prepared following theprocedures described for Example 441.

Example 4506-Bromo-2-(2-isopropylphenoxy)-N-(4-(trifuoromethyl)thiazol-2-yl)pyridin-3-amine

Example 450a 6-Bromo-2-(2-isopropylphenoxy)pyridin-3-amine

A solution of N-bromosuccinimide (2.32 g, 13.0 mmol) in DMF (20 ml) wasadded to a cold (−20° C.) solution of Intermediate 2 (2.76 g, 11.4 mmol)in DMF (25 mL). The reaction rapidly turned dark red. HPLC analysisafter 5 min showed that the reaction was complete. The reaction wasquenched with a freshly prepared solution of sodium thiosulfate (40 mL,10% aqueous). A precipitate formed. The mixture was warmed to rt and wasdiluted with water (60 mL). The solid was filtered, washed with waterand dried overnight under reduced pressure to give Example 450a (3.82 g,96% yield) as brown solid. [M+H]⁺=321.14. ¹H NMR (500 MHz, CDCl₃) δ ppm1.40 (s, 9 H),3.91 (s, 2 H), 6.93 (m, 2 H), 7.00 (d, J=8.07 Hz, 1 H),7.12 (t, J=7.73 Hz, 1 H), 7.20 (t, J=7.73 Hz, 1 H), 7.41 (d, J=8.07 Hz,1 H).

Example 450b 1-(6-Bromo-2-(2-isopropylphenoxy)pyridin-3-yl)thiourea

To a solution of Example 450a (1.7 g, 5.54 mmol) in THF (35 mL) at rtwas added benzoylisothiocyanate (0.83 mL, 6.09 mmol). After heating thisreaction mixture at 40° C. for 2 h, methanol (10 mL) and 1.0 M KOH (10mL) was added and the reaction was stirred at 40° C. for an additional 3h. The reaction was taken up in EtOAc (200 mL) and washed once with50:50 sat. aq. NaCl:sat. aq. NaHCO₃ (200 mL) and once with water (200mL). The organic layer was dried over MgSO₄, filtered and concentrated.The residue was taken up in Et₂O (˜25 mL) and, while sonicating, hexane(˜50 mL) was added slowly to provide a precipitate. The solid wascollected, rinsed with 25% Et₂O in hexane (˜10 mL) and dried undervacuum to give Example 450b (1.89 g). (M+H)⁺=366.2, 368.2 (Br isotopicpattern).

Example 450

To a solution of Example 450b (1.2 g, 3.28 mmol) in ethanol (20 ml) in apressure vessel was added 2,6-lutidine (1.0 mL) and3-bromo-l,1,1,1-trifluoropropan-2-one (0.63 g, 3.28 mmol). The vesselwas sealed and the reaction was heated at 90° C. for ˜18 h. Aftercooling to rt, solvent was removed. The residue was taken up in Et₂O andsolids removed. After reducing the solvent again, purification by flashchromatography (silica gel, 10% EtOAc in hexanes) provided Example 450(1.48 g). (M+H)+=458.2, 460.2 (Br isotopic pattern).

Example 4512-(2-Isopropylphenoxy)-N-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

To a solution of Example 450 (20 mg, 0.044 mmol) in methanol (5 mL) wasadded 10% Pd/C (50% H₂O type, 5 mg). The flask was fitted with ahydrogen balloon and H₂ was bubbled through the solution for 5 min andthen the reaction was stirred under H₂ for 3 h. The reaction wasfiltered through Celite® and eluted with methanol. Purification by prepHPLC (Method A) provided Example 451 (13 mg) as an off white solid.(M+H)⁺=380.3.

Example 4526-Cyano-2-(2-isopropylphenoxy)-N-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

To a solution of Example 450 (200 mg, 0.437 mmol) in dry, nitrogendegassed DMF (4 mL) at rt was added Zn(CN)₂ (102 mg, 0.874 mmol) and Zndust (8.5 mg, 0.131 mmol). After the reaction was degassed for anadditional 5 min, Pd (tBu₃P)₂ (20 mg, 0.039 mmol) was added and thereaction was heated to 60° C. overnight (˜18 h). The reaction was cooledto rt, diluted with EtOAc and washed twice with saturated aqueousNaHCO₃. The organic layer was dried over MgSO₄, filtered andconcentrated. Purification by flash chromatography (40 g ISCO silica gelcartridge, 0 to 10% EtOAc in hexane single step gradient) providedExample 452 (178 mg). (M+H)⁺=405.3.

Example 4536-Dimethylamino-2-(2-isopropylphenoxy)-N-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

To a solution of Example 450 (34 mg, 0.074 mmol) in dry, nitrogendegassed toluene (1.0 mL) at rt was added Me₂NH (2.0 M in THF, 170 μL,0.34 mmol), KOtBu (1.0 M in THF, 200 μL, 0.2 mmol) and Pd(tBu₃P)₂ (5 mg,0.0098 mmol). The reaction was sealed and heated to 70° C. for 3 h. Thereaction was diluted with hexane (0.25 mL), loaded to a prep TLC plate(20×20 cm²×2000 μm) and eluted up the plate with 15% EtOAc in hexanes.After identification by UV and HPLC, the desired material was removedfrom the plate and eluted from the silica gel with 3:1dichlormethane:EtOAc. Repurification by prep HPLC (YMC-PAC-ODS column(20 mm×100 mm) at 20 mL/min, 10 min gradient from 20% to 100% B wheresolvent A is 10% MeOH/Water+0.1% TFA and solvent B is 90%MeOH/Water+0.1% TFA) provided Example 453 (5.5 mg). (M+H)⁺=423.3.

Example 4546-(4-Methoxybenzyl)amino-2-(2-isopropylphenoxy)-N-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example 454 was prepared using the method described for Example 453except using 4-methoxybenzylamine in place of dimethylamine.(M+H)⁺=515.3.

Example 4556-Amino-2-(2-isopropylphenoxy)-N-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example 453 (≦0.085 mmol, semi-crude) was taken up 50% TFA indichloromethane and allowed to set overnight. Solvent was removed undervacuum and purification by prep HPLC (YMC-PAC-ODS column (20 nm×100 mm)at 20 mL/min, 10 min gradient from 20% to 100% B where solvent A is 10%MeOH/Water+0.1% TFA and solvent B is 90% MeOH/Water+0.1% TFA) providedExample 455 (7 mg). (M+H)⁺=395.3.

Example 4565-Bromo-2-(2-isopropylphenoxy)-N-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example 456a 5-Bromo-2-(2-tert-butylphenoxy)pyridine-3-amine

To a solution of 5-bromo-2-chloro-3-nitropyridine (4.9 g, 20.7 mmol) and2-isopropylphenol (2.87 g, 21.1 mmol) in NMP (45 ml) in a 500 mLpressure vessel at rt was added K₂CO₃ (5.7 g). The reaction was fittedwith a stir bar, sealed and heated at 115° C. for 48 h. The reaction wasextracted with Et₂O (350 mL), washing with water (3×). The aqueouslayers were then back extracted with Et₂O. The combined organic layerswere dried over MgSO₄, filtered and concentrated. The crude material wasthen flash filtered through silica gel, eluting with 10% EtOAc inhexanes. Solvent was removed under vacuum. The residue was taken up intoMeOH (150 mL) to which Zn powder (6 g) was added followed by slowaddition of NH₄Cl (6 g). After stirring at rt for 20 min, the reactionwas filtered through Celite® and the pad washed with MeOH. The solventwas remove under vacuum & the residue taken up into dichloromethane. Thesolid material formed was filtered off and discarded. Hexane was addedto the dichloromethane eluent to initiate precipitation. The solidformed here was collected by filtration to provide Example 456a (385mg). (M+H)⁺=307.3, 309.3 (Br isotopic pattern).

Example 456b 1-(5-Bromo-2-(2-isopropylphenoxy)pyridin-3-yl)thiourea

Prepared from Example 456a (385 mg, 1.25 mmol) as described previouslyfor Example 451b to afford Example 456b (405 mg). (M+H)⁺=366.2, 368.2(Br isotopic pattern).

Example 456

Example 456 (380 mg) was prepared from Example 456b (405 mg, 1.25 mmol)as described previously for Example 451. (M+H)⁺=458.2, 460.2 (Brisotopic pattern).

Example 4575-Cyano-2-(2-isopropylphenoxy)-N-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Prepared from Example 456 (103 mg, 0.225 mmol) as described previouslyfor 452 to afford Example 457 (83 mg). (M+H)⁺=405.3.

Example 4585-Dimethylamino-2-(2-isopropylphenoxy)-N-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Prepared from Example 456 (25 mg, 0.055 mmol) as described previouslyfor Example 453 to afford Example 458 (14 mg). (M+H)⁺=423.3.

Example 4595-(4-Methoxybenzyl)methylamino-2-(2-isopropylphenoxy)-N-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Prepared from Example 456 (25 mg, 0.055 mmol) as described previouslyfor 453 except using (4-methoxybenzyl)methylamine in place ofdimethylamine to afford Example 459 (16 mg). (M+H)⁺=529.3.

Example 460N-(2-(2-tert-Butylphenoxy)thiophen-3-yl)-4-(pentafluoroethyl)thiazol-2-amine

Example 460a 1-(2-(2-tert-Butylphenoxy)thiophen-3-yl)thiourea

Prepared from Intermediate 3 (2.0 g, 8.10 mmol) as described previouslyfor Example 450b to afford Example 460a (1.8g). (M+H)⁺=307.3.

Example 460

Prepared from Example 460a (30 mg, 0.098 mmol) and1-bromo-3,3,4,4,4-pentafluorobutan-2-one (0.098 mmol) following theprocedure for the preparation of Example 450 to provide Example 460 (26mg). (M+H)⁺=449.2.

Examples 461-464 listed in Table 16 were prepared following theprocedures described for Example 460 using the commercially availableα-haloketone shown. TABLE 16 Example α-haloketone Structure (M + H)⁺ 461

399 462

471 463

403 464

407

Examples 465-466 listed in Table 17 were prepared following theprocedures described for Example 450 using Intermediates 5-7 and theappropriate α-haloketone. TABLE 17 Example α-haloketone Structure (M +H)⁺ 465

396 466

494 467

480 468

410 469

398

Example 4702-(2-tert-Butylphenoxy)-N-(3-(phenylthiomethyl)-1,2,4-thiadiazol-5-yl)pyridin-3-amine

Example 470 was prepared from2-(2-tert-butylphenoxy)-3-isothiocyanatopyridine (Example 1a) followingthe procedures described for Example 56. (M+H)⁺=449.

Example 4712-(2-tert-Butylphenoxy)-N-(3-(phenylsulfinylmethyl)-1,2,4-thiadiazol-5-yl)pyridin-3-amine

A mixture of2-(2-tert-butylphenoxy)-N-(3-(phenylthiomethyl)-1,2,4-thiadiazol-5-yl)pyridin-3-amine(Example 470) (250 mg, 0.56 mmol), peracetic acid (32% wt/v, 132 μL,0.56 mmol in DCM (3 mL) was stirred at rt for 2 h. The reaction mixturewas diluted in ethyl acetate and washed with saturated sodiumbicarbonate. The organic phase was separated, dried (MgSO₄), filteredand evaporated. The crude product was purified by preparative HPLC togive Example 471. (M+H)⁺=465; ¹H NMR (400 MHz, DMSO d₆) δ ppm 1.29 (s, 9H), 4.33 (d, J=13.13 Hz, 1 H), 4.42 (d, J=13.13 Hz, 1 H), 6.91 (td,J=7.84, 1.51 Hz, 1 H), 7.08 (dd, J=7.84, 4.80, 1H), 7.16 (dt, J=7.58,1.52, 1H), 7.22 (td, J=7.32, 1.76, 1H), 7.41 (dd, J=7.83, 1.52 Hz, 1 H),7.5-7.7 (m, 5H), 7.75 (dd, J=4.80, 1.51 Hz, 1 H), 8.45 (dd, J=7.83, 1.51Hz, 1H), 10.84 (s, 1 H).

Example 472 4-(2-(2-tert-Butylphenoxy)pyridin-3-yl)thiosemicarbazide

A mixture of sodium hydride (140 mg, 3.51 mmol) and cyanamide (148 mg,3.51 mmol) in EtOH (10 mL) was stirred at rt for 15 min.2-(2-tert-butylphenoxy)-3-isothiocyanatopyridine (Example 1a) (1 g, 3.51mmol) was added and mixture was stirred for 2 h. The solvent was removedand the residue was dissolved in EtOAc (10 mL), bromine (562 mg, 3.51mmol) was added and mixture was stirred for 18 h. The reaction mixturewas washed with water, dried (anh. MgSO₄), filtered and evaporated. Thecrude material was purified by flash chromatography on silica gel (10%EtOAc/Hexanes) and by preparative HPLC to give Example 472 (5 mg, TFAsalt) as a white powder. (M+H)⁺=405. ¹H NMR (400 MHz, DMSO d₆) δ ppm1.30 (s, 9 H), 6.93 (dd, J=7.83, 1.52 Hz, 1 H), 7.1-7.3 (m, 3 H), 7.43(dd, J=7.83, 1.77 Hz, 1 H), 7.83 (dd, J=4.80, 1.51 Hz, 1 H), 8.65 (dd,J=7.84, 1.51 Hz, 1 H), 11.13 (s, 1 H).

Example 473N-(5-((Benzyl(methyl)amino)methyl)-1,3,4-thiadiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

Example 473a2-(2-tert-Butylphenoxy)-N-(5-(chloromethyl)-1,3,4-thiadiazol-2-yl)pyridin-3-amine

Example 473a was synthetized following the procedure for Example 1 using4-(2-(2-tert-butylphenoxy)pyridin-3-yl)thiosemicarbazide (Example 1b)with chloroacetyl chloride.

Example 473

A mixture of Example 473a (25 mg, 0.07 mmol), N-benzylmethylamine (45μL, 0.35 mmol) in DMF (2 mL) was agitated at rt for 3 h. The crudematerial was purified by preparative HPLC to give Example 473 (11 mg, 2TFA salt) as a white solid. (M+H)⁺=460. ¹H NMR (400 MHz, DMSO d₆) δ ppm1.30 (s, 9 H), 2.07 (s, 3H), 6.93 (d, J=9.09 Hz, 1 H), 7.1-7.3 (m, 3H),7.4-7.5 (m, 4H), 7.73 (d, J=4.29 Hz, 1 H), 7.96 (d, J=8.08 Hz, 1 H),8.18 (d, J=8.33 Hz, 1 H) 8.83 (d, J=7.08 Hz, 1 H).

Example 474N-(5-((4-Benzylpiperazin-1-yl)methyl)-1,3,4-thiadiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

Example 474 was prepared following the procedures described for Example473. (M+H)⁺=515.

Examples 475-476 listed in Table 18 were prepared following theprocedures described for Example 1 using Intermediates 8-9. TABLE 18Exam- ple Structure (M + H)⁺ 475

460 476

453

Examples 477-495 listed in Table 6 were prepared following the proceduredescribed for Example 172.

Example 496 Ethyl3-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-1-(cyclopropylmethyl)-1H-pyrazole-5-carboxylate

Example 496a3-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-1-(cyclopropylmethyl)-1H-pyrazole-5-carboxylicacid

To a solution of3-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-1-(cyclopropylmethyl)-1H-pyrazole-5-carbonitrile(Example 184) (64.9 mg, 0.17 mmol) in water (1 mL) was added the aqueoussodium hydroxide solution (2M in water, 418 μL, 0.84 mmol) and themixture was heated at 200° C. for 10 min in the microwave. After coolingto 23° C., 1N HCl was added slowly till pH=2 and the mixture wasextracted with ethyl acetate (3×). Combined organic layers were washedwith water, brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by preparative HPLC to yield 45 mg (65%TFA salt) of Example 496a.

(M+H)⁺=407.

Example 496

To a solution of3-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-1-(cyclopropylmethyl)-1H-pyrazole-5-carboxylicacid (Example 20a) (38 mg, 0.073 mmol) in DCM (730 μL) was added1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (34 mg, 0.156 mmol),1-hydroxybenzotriazole hydrate (24 mg, 0.156 mmol) and ethanol (10 μL,0.156 mmol. The mixture was stirred for 3 days at 23° C. thenconcentrated in vacuo. 1N HCl was added (25 mL) and the aqueous layerwas extracted with ethyl acetate (3×). The combined organic layers werewashed with water (50 mL), brine (50 mL) and dried (anh. Na₂SO₄),filtered and concentrated in vacuo. The residue was purified preparativeHPLC to yield 26 mg (81%, TFA salt) of Example 496. (M+H)⁺=435. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.44 (s, 1H), 8.42 (dd, 1H, J=7.8, 1.5 Hz),7.46 (dd, 1H, J=4.8, 1.5 Hz), 7.40 (dd, 1H, J=7.8, 1.5 Hz), 7.21 (td,1H, J=7.8, 1.7 Hz), 7.13 (td, 1H, J=7.8, 1.5 Hz), 7.00 (dd, 1H, J=7.9,4.8 Hz), 6.89(dd, 1H, J=7.8, 1.2 Hz), 6.63 (s, 1H), 4.31-4.26 (m, 4H),1.31 (s, 9H), 1.31-1.26 (m, 1H), 1,29 (t, 3H, J=7,1 Hz), 0.49-0.46 (m,2H), 0.40-0.36 (m, 2H).

Example 4972-(2-tert-Butylphenoxy)-N-(5-(3-(3-(dimethylamino)-2,2-dimethylpropoxy)phenyl)-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

A suspension of PPh₃-resin (3.0 mmol/g resin, 167 mg, 0.5 mmol) in THFwas stirred at rt for 15 min and3-(dimethylamino)-2,2-dimethylpropan-1-ol (38 μL, 0.24 mmol) and DBAD(35 mg, 0.15 mmol) were added. The mixture was stirred at rt for 30 minand3-(2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-4-(trifluoromethyl)-1H-imidazol-5-yl)phenol(Example 117, 50 mg, 0.10 mmol) was added. The mixture was stirred at rtfor 2 h. Another 38 μL of 3-(dimethylamino)-2,2-dimethylpropan-1-ol and35 mg of DBAD were added and then stirred at rt for 30 min. LC-MS showedthe formation of desired product and two by-products. The reaction wasfiltered and the filtrate was evaporated to give the crude product.Purification of the crude product by reverse phase preparative HPLCprovided Example 497 as a colorless film (13.5 mg). (M+H)⁺=599.2.

Example 498N-(5-(4-(Benzyloxy)phenyl)-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

To a solution of compound 107a (340 mg, 0.72 mmol) in toluene/methanol(2:1, 4 mL) was added 4-benzyloxy phenyl boronic acid (328 mg, 1.44mmol), 2 M Na₂CO₃ solution (1.44 ml, 2.88 mmol). The mixture was bubbledwith nitrogen, added catalyst Pd(PPh₃)₄ (83 mg, 0.072 mmol) and heatedat 85° C. overnight. The mixture was diluted with EtOAc, washed withbrine, dried over magnesium sulfate, filtered and evaporated to give thecrude product. Purification of crude product by flash chromatography (40g silica, 0-20% EtOAc/hexane) provided Example 498 (245 mg) as a whitefoam. (M+H)⁺=576.3.

Example 4994-(2-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-4-(trifluoromethyl)thiazol-5-yl)phenol

To a solution of Example 498 (164 mg, 0.28 mmol) in MeOH/EtOAc (1:1, 10mL) was added a few drops of Raney Ni in water. The mixture was stirredunder hydrogen atmosphere at rt overnight. The reaction was filteredthrough a layer of Celite®. The filtrate was concentrated to give thecrude product. Purification of the crude product by flash chromatography(silica, 0-50% EtOAc/hexane) provided Example 499 (105 mg) as a whitefoam. (M+H)⁺=486.0.

Example 5002-(2-tert-Butylphenoxy)-N-(5-(4-(3-(dimethylamino)-2,2-dimethylpropoxy)phenyl)-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example 500 was prepared according to a similar procedure described forExample 217 from Example 499 and3-(dimethylamino)-2,2-dimethylpropan-1-ol. Example 500 was obtained as acolorless film (3 mg). (M+H)⁺=599.3.

Examples 501-502 listed in Table 19 were prepared following theprocedure(s) indicated. TABLE 19 Procedure(s) Example Used Structure(M + H)⁺ 501 Example 94

515 502 Example 106

535

Example A1-A50 listed in Table 20 were prepared following theprocedure(s) indicated. TABLE 20 Procedure(s) Example Used Structure(M + H)⁺ A1  Example 315

451.2 A2  Example 315

501.2 A3  Example 315

501.1 A4  Example 315

501.1 A5  Example 315

472.1 A6  Example 315

451.1 A7  Example 315

465.1 A8  Example 315

435.1 A9  Example 315

465.1 A10 Example 315

463.1 A11 Example 315

423.1 A12 Example 315

461.3 A13 Example 315

489.3 A14 Example 315

485.3 A15 Example 315

496.3 A16 Example 315

487.3 A17 Example 315

485.4 A18 Example 315

496.3 A19 Example 315

472.3 A20 Example 315

487.3 A21 Example 315

485.4 A22 Example 315

437.3 A23 Example 315

461.3 A24 Example 315

555.3 A25 Example 361

451.1 A26 Example 361

506.2 A27 Example 361

576.3 A28 Example 361

549.2 A29 Example 361

508.2 A30 Example 361

525.2 A31 Example 361

550.2 A32 Example 361

506.2 A33 Example 361

549.2 A34 Example 361

591.3 A35 Example 361

536.2 A36 Example 361

520.1 A37 Example 361

520.1 A38 Example 361

494.2 A39 Example 361

566.2 A40 Example 361

506.1 A41 Example 361

520.2 A42 Example 361

449.1 A43 Example 361

549.2 A44 Example 361

534.2 A45 Example 361

521.1 A46 Example 361

534.1 A47 Example 361

507.1 A48 Example 361

521.1 A49 Example 361

493.1 A50 Example 361

507.2

Example A512-(2-tert-Butylphenoxy)-N-(5-(3-methyl-1,2,4-oxadiazol-5-yl)-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example A51a2-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-4-(trifluoromethyl)thiazole-5-carboxylicacid

Example A51a was prepared from ethyl2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-4-(trifluoromethyl)thiazole-5-carboxylate(Example 238) according to the procedure described for Example 251a.

Example A51

A mixture of Example A51a (40 mg, 0.091 mmol), N-hydroxyacetamidine (10mg, 0.14 mmol, DIC (43 μL, 0.27 mmol), HOBt (12 mg, 0.091 mmol) inacetonitrile (1.5 mL) was heated at 160° C. under microwave for 15 min.The reaction was cooled and concentrated. The residue was purified byreverse preparative HPLC to give Example A51 (25 mg). (M+H)⁺=476.2.

Example A522-(2-tert-Butylphenoxy)-N-(5-(3-phenyl-1,2,4-oxadiazol-5-yl)-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example A52 was prepared following the procedure described for ExampleA51 as a yellow film. (M+H)⁺=538.3.

Example A532-(2-tert-Butylphenoxy)-N-(5-(5-methyl-1,2,4-oxadiazol-3-yl)-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example A53a(Z)-2-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-N′-hydroxy-4-(trifluoromethyl)thiazole-5-carboxamidine

A mixture of2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-4-(trifluoromethyl)thiazole-5-carbonitrile(Example 404, 177 mg, 0.42 mmol), hydroxylamine hydrochloride salt (145mg, 2.1 mmol), DIPEA (732 μL, 4.2 mmol) in ethanol (5 mL) was heated at60° C. for 5 h. The reaction was diluted with ethyl acetate and washedwith brine. The organic layer was separated and evaporated to give thecrude product. Purification of the crude product by flash chromatography(silica, 0-80% EtOAc/hexane gradient) gave Example A53a (120 mg) aswhite crystals. (M+H)⁺=452.1.

Example A53

A mixture of Example A53a (40 mg, 0.091 mmol), acetic acid (10 μL, 0.16mmol), DIC (43 μL, 0.27 mmol), HOBt (12 mg, 0.091 mmol) in acetonitrile(1.5 mL) was heated at 160° C. under microwave for 15 min. The reactionwas cooled and concentrated. The residue was purified by reversepreparative HPLC to give Example A53 (13 mg). (M+H) +=476.

Example A54(2-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-5-phenylthiazol-4-yl)methanol

Example A54 was prepared according to a similar procedure described forExample 251. (M+H)⁺=432.2.

Example A552-(2-tert-Butylphenoxy)-N-(4-(ethoxymethyl)-5-phenylthiazol-2-yl)pyridin-3-amine

Example A55a2-(2-tert-Butylphenoxy)-N-(4-(chloromethyl)-5-phenylthiazol-2-yl)pyridin-3-amine

To a solution of Example A54 (170 mg, 0.39 mMol) in DCM (6 mL) at rt wasadded sulfonyl chloride (114 gl, 1.57 mMol). The mixture was stirred atrt for 2 h. The solvent was removed to give Example A55a (170 mg) as ayellow foam. (M+H)⁺═450.2.

Example A55

A small piece of sodium was added to ethanol (2 mL) and stirred at rtuntil the sodium was completely disappeared to give a light yellowsolution. A solution of Example A55a (20 mg) in THF (1 mL) was added.The reaction was stirred at rt overnight and then quenched with water.The mixture was concentrated and the residue was partitioned betweenEtOAc and brine. The organic layer was isolated and evaporated. Theresidue was purified by reverse phase preparative HPLC to Example A55(2.5 mg) as a colorless film. (M+H)⁺═486.0.

Example A56-A124 listed in Table 21 were prepared following theprocedure(s) indicated. TABLE 21 Procedure(s) Example Used Structure(M + H)⁺ A56 Example A55

543.2 A57 Example A55

543.2 A58 Example A55

488.2 A59 Example A55

531.2 A60 Example A55

490.1 A61 Example A55

446.2 A62 Example 217

380.3 A63 Example 217

382.3 A64 Example 217

366.3 A65 Example 217

368.3 A66 Example 217

340.3 A67 Example 217

408.4 A68 Example 217

408.3 A69 Example 217

394.3 A70 Example 217

368.4 A71 Example 217

354.3 A72 Example 217

410.4 A73 Example 217

382.4 A74 Example 217

452.4 A75 Example 323

380.3 A76 Example 323

366.3 A77 Example 323

408.4 A78 Example 323

512.3 A79 Example 323

526.3 A80 Example 323

458.3 A81 Example 323

416.3 A82 Example 323

472.3 A83 Example 323

456.3 A84 Example 323

430.3 A85 Example 323

458.3 A86 Example 323

444.3 A87 Example 323

569.2 A88 Example 323

569.2 A89 Example 323

529.3 A90 Example 323

528.1 A91 Example 323

528.2 A92 Example 323

542.1 A93 Example 323

471.1 A94 Example 323

514 A95 Example 323

514 A96 Example 323

513.1 A97 Example 323

542.1 A98 Example 323

486 A99 Example 323

576 A100 Example 323

513.1 A101 Example 323

488.1 A102 Example 323

518 A103 Example 323

502.1 A104 Example 323

556 A105 Example 323

530.1 A106 Example 323

502.1 A107 Example 323

502.2 A108 Example 323

488.2 A109 Example 323

530.2 A110 Example 323

516.2 A111 Example 323

462.3 A112 Example 323

476.3 A113 Example 323

474.1 A114 Example 323

460.3 A115 Example 361

465.4 A116 Example 361

479.4 A117 Example 361

481.3 A118 Example 361

423.3 A119 Example 361

437.3 A120 Example 361

451.3 A121 Example 361

509.3 A122 Example 361

453.2 A123 Example 361

537.2 A124 Example 361

439.2

Example A125 tert-Butyl2-(2-tert-butylphenoxy)pyridin-3-yl(5-(3-(3-(dimethylamino)-2,2-dimethylpropoxy)phenyl)-4-(trifluoromethyl)thiazol-2-yl)carbamate

Example A125a tert-Butyl5-bromo-4-(trifluoromethyl)thiazol-2-yl(2-(2-tert-butylphenoxy)pyridin-3-yl)carbamate

A mixture ofN-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine(Example 323a, 135 mg, 0.29 mMol), BOC₂O (75 mg, 0.34 mMol), DMAP (5 mg)and DIPEA (59 gl, 0.34 mMol) in THF (5 mL) was stirred at rt for 5 h.The solvent was removed and the residue was purified by flashchromatography (silica, 0-50% EtOAc/hexane gradient) provided ExampleA125a (149 mg) as a white foam. (M+H)⁺═574.2.

Example A125b tert-Butyl2-(2-tert-butylphenoxy)pyridin-3-yl(5-(3-hydroxyphenyl)-4-(trifluoromethyl)thiazol-2-yl)carbamate

Example A125b was prepared from Example A125a according to a similarprocedure described for2-(2-tert-butylphenoxy)-N-(4-(trifluoromethyl)-5-(4-(trifluoromethyl)phenyl)thiazol-2-yl)pyridin-3-amine(Example 323).

Example 125

To a suspension of PS-PPh₃ (124 mg, 0.37 mMol) in THF (1 mL) was added asolution of Example A125b (50 mg, 0.085 mMol) in THF (0.5 mL) and wasstirred at rt for 5 min. A solution of DBAD (62 mg, 0.27 mMol) in THF(0.5 mL) was added and stirred at rt for 5 min. Finally3-(dimethylamino)-2,2-dimethylpropan-1-ol (32 gl, 0.21 mMol) was addedand the mixture was stirred at rt overnight. The reaction was filteredand the filtrate was concentrated. The residue was purified by flashchromatography (silica, 0-100% EtOAc/hexane gradient) provided example125 as an off-white solid (40 mg). (M+H)⁺═712.3.

Example A1262-(2-tert-Butylphenoxy)-N-(5-(3-((1-methylpiperidin-4-yl)methoxy)phenyl)-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example A126 was prepared according to a similar procedure described forExample 500. (M+H)⁺═597.3.

Example A127N-(5-(1H-1.,2,4-Triazol-3-yl)-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

A solution of2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-4-(trifluoromethyl)thiazole-5-carboxamide(Example 269, 33 mg) in N,N-dimethylformamide dimethyl acetal (0.5 mL)was stirred at rt for 1 h. The reaction was concentrated and the residuewas treated with HOAc (1.0 mL) and hydrazine monohydrate (7 gl) at 70°C. for 1 h. The solvent was removed and the residue was diluted withEtOAc, washed with sodium bicarbonate solution, dried with magnesiumsulphate and evaporated to give the crude product. Purification of thecrude product by reverse phase preparative HPLC provided Example A127(17 mg) as a colorless film. (M+H)⁺═461.3.

Example A1322-(2-tert-butylphenoxy)-N-(5-(2-methyl-2H-tetrazol-5-yl)thiazol-2-yl)pyridin-3-amine

A mixture ofN-(5-(1H-tetrazol-5-yl)-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine(Example 407, 19 mg, 0.048 mMol), MeI (5 gl), sodium bicarbonate (8 mg)and acetone was stirred at rt overnight. The solvent was removed and theresidue was purified by reverse phase preparative HPLC to give ExampleA132 as a colorless film (16 mg). (M+H)⁺═408.2.

Example A1332-(2-tert-butylphenoxy)-N-(5-(2-methyl-2H-tetrazol-5-yl)-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example A133 was prepared fromN-(5-(1H-tetrazol-5-yl)-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine(Example 404) following the procedure described for Example A132.

Example A128-A131 and A134-153 listed in Table 22 were preparedfollowing the procedure(s) indicated. TABLE 22 Procedure(s) Example UsedStructure (M + H)⁺ A128 Example A125

503.3 A129 Example A125

545.1 A130 Example A125

515.1 A131 Example A125

505.1 A134 Example 272

445.2 A135 Example 272

459.2 A136 Example 272

529.3 A137 Example 272

541.3 A138 Example 272

557.3 A139 Example 272

515.3 A140 Example 390

459.2 A141 Example 390

473.2 A142 Example 390

459.2 A143 Example 390

543.3 A144 Example 390

529.3 A145 Example 390

571.3 A146 Example 390

501.2 A147 Example 390

529.3 A148 Example 251

509.3 A149 Example 251

474.3 A150 Example 404

483.3 A151 Example A132

526.2 A152 Example A132

540.2 A153 Example A132

540.2

Example A1541-(2-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-4-(trifluoromethyl)thiazol-5-yl)ethanone

Example A154a2-(2-tert-Butylphenoxy)-N-(5-(1-ethoxyvinyl)-4-(trifuoromethyl)thiazol-2-yl)pyridin-3-amine

A solution ofN-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine(Example 323a, 1.3 g, 2.75 mMol) in dioxane (30 mL) was added tributyl(1-ethoxyvinyl)tin (1.1 mL, 3.3 mMol) was degassed and Pd(PPh₃)₄ (160 mg,0.14 mMol) was added. The mixture was degassed and heated at 100° C.overnight. The mixture was concentrated on vacuum, dissolved in EtOAcand treated with saturated KF solution. The solid was removed byfiltering through a pad of Celite®. The filtrate was extracted withEtOAc. The organic layers were combined, washed with bring, dried overmagnesium sulfate and concentrated to give crude Example A154a (1.12 g)as a brown oil.

Example A154

Example A154a (crude, 1.12 g) was dissolved in diethyl ether (30 mL) andtreated with 4 N HCl/ether solution at rt for 2 h. The solvent wasremoved and the residue was purified by flash chromatography (120 g ISCOsilica gel column, 0-70% EtOAc/hexane) to give Example A154 (890 mg) asa yellow solid.

Example A1552-(2-tert-Butylphenoxy)-N-(5-(prop-1-en-2-yl)-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

To a solution of Example A154 (105 mg, 0.24 mMol) in THF (3 mL) at 0° C.was added Tebbe reagent (C₁₃H₁₈AlClTi) (0.5 M in toluene, 580 gl, 0.29mmol). The mixture was stirred at 0° C. for 15 min and was allowed towarm to rt and stirred at rt for 10 days. The reaction was diluted withdiethyl ether (10 mL) and quenched with 5 drops of 1 N NaOH. The mixturewas dried over sodium sulfate and filtered. The filtrate wasconcentrated and purified by flash chromatography (12 g ISCO silica gelcolumn, 0-40% EtOAc/hexane) to give Example A155 (24 mg) as a yellowfilm. (M+H)⁺═434.3.

Example A1562-(2-tert-Butylphenoxy)-N-(5-isopropyl-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

A mixture of Example A155 (15 mg) and 10% Pd/C (5 mg) in methanol (2 mL)was stirred under hydrogen atmosphere for 3 h. The mixture was filteredand the filtrate was concentrated to give Example A156 (12 mg) as acolorless film. (M+H)⁺═436.3.

Example A1572-(2-tert-Butylphenoxy)-N-(4-(trifluoromethyl)-5-vinylthiazol-2-yl)pyridin-3-amine

Example A157 was prepared fromN-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine(Example 323a) according to the procedure described for Example A154a.(M+H)⁺═420.3.

Example A1582-(2-tert-Butylphenoxy)-N-(5-ethyl-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example A158 was prepared from Example A 157 according to the proceduredescribed for Example A156. (M+H)⁺═420.3.

Example A1592-(2-(2-(2-tert-Butylphenoxy)pyridin-3-ylamino)-4-(trifluoromethyl)thiazol-5-yl)ethanol

A solution of Example A157 (105 mg, 0.25 mMol) in THF (1.5 mL) at 0° C.was added BH₃-THF (1.0 M, 500 gl, 0.5 mMol). The mixture was stirred at0° C. for 1 h, warmed to rt and stirred at rt for 1 h. The reaction wascooled to 0° C. and 1 N NaOH solution (750 gl, 0.75 mMol) was addedfollowed by H₂O₂ solution (35%, 500 μl). The mixture was stirred at rtovernight. The mixture was extracted with EtOAc. The organic layers werecombined, washed with saturated sodium bicarbonate solution, brined,dried over sodium sulfate and filtered. The filtrate was concentratedand purified by flash chromatography (40 g ISCO silica gel column,0-100% EtOAc/hexane) to give Example A159 (57 mg) as a white foam.(M+H)⁺=438.1.

Example A1602-(2-tert-Butylphenoxy)-N-(5-((isobutyl(methyl)amino)methyl)-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example A160 was prepared according to the procedure described forExample 272. (M+H)⁺═493.2.

Example A161N-(4-tert-Butyl-5-((isobutyl(methyl)amino)methyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine.

Example A161 was prepared from(4-tert-butyl-2-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)thiazol-5-yl)methanol(Example 252) and isobutyl methyl amine according to the proceduredescribed for Example 272. (M+H)⁺=493.2.

Example A162N-(4-tert-Butyl-5-(1H-imidazol-1-yl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine

A mixture ofN-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine(Example 323a, 30 mg) and imidazole (100 mg) in dioxane (200 gl) washeated at 100° C. for 18 h. The reaction was diluted with methanol andpurified by reverse preparative HPLC to give Example A162 (11 mg) as anoff-white solid. (M+H)⁺═460.1.

Example A162-A165 listed in Table 23 were prepared fromN-(5-bromo-4-(trifluoromethyl)thiazol-2-yl)-2-(2-tert-butylphenoxy)pyridin-3-amine(Example 323a) using the same procedure described for Example A161.TABLE 23 Example Structure (M + H)⁺ A163

507.1 A164

507.1 A165

546.1

Example A1662-(2-(2-Methylbut-3-en-2-yl)phenoxy)-N-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example A166a 2-(2-Methylbut-3-en-2-yl)phenol

A mixture of 1-(3-methylbut-2-enyloxy)benzene (2.8 g, 11.1 mMol), Ac₂O(25 mL) and AcOK (2.8 g) were placed in a steel bomb, degassed andbubbled with N₂ for 10 min. The reaction was heated at 200° C. for 16 h.The reaction was cooled to rt, quenched with water (1 50 mL) and stirredat rt for 1 h. The mixture was extracted with diethyl ether. Thecombined organic layers were washed with water, dried over magnesiumsulfate and evaporated. The residue was dissolved in THF:MeOH:H₂O(3:2:1, 200 mL), adjusted pH═9 with KOH and stirred at rt overnight. Tothe mixture was added HCl until pH═6 and then NaHCO₃ till neutralized.The mixture was extracted with diethyl ether. The combined organiclayers were washed with water, dried over magnesium sulfate andevaporated to give the crude product. Purification of the crude productby flash chromatography (20 g silica gel, 5% EtOAc/hexane) providedExample A166a (1.55 g).

Example A166b 2-(2-(2-Methylbut-3-en-2-yl)phenoxy)pyridin-3-amine

A mixture of Example A166a (1.55 g, 9.51 mMol), 2-fluoro-3-nitropyridine(1.34 g, 9.51 mMol) and potassium carbonate (1.55 g) in dioxane (5 mL)was stirred at rt overnight. The reaction was diluted with EtOAc (50mL), filtered and evaporated. The residue was combined with MeOH (5 mL),HOAc (7.5 mL), i-PrOH (12.5 mL) and Fe (2 g). The mixture was heated at100° C. for 2.5 h. The solvent was remover and the residue waspartitioned between EtOAc and 1 N NaOH. The mixture was filtered throughCelite® and the Celite® cake was washed with EtOAc. The organic layerwas separated from the filtrate, washed with water, dried over magnesiumsulfate, filtered and evaporated to give the crude product. Purificationof the crude product by flash chromatography (20 g silica gel, 5%EtOAc/hexane) provided Example A166b (1.3 g). (M+H)⁺═255.

Example A166 was prepared from Example A166b following the sameprocedure as for Example 217. (M+H)⁺═406.1.

Example A1672-(2-Bromophenoxy)-N-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example A167 was prepared from 2-fluoro-3-nitropyridine and2-bromophenol following the same procedure as for Example A166.(M+H)⁺═415.9, 418.0.

Example A1682-(2-Iodophenoxy)-N-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example A168 was prepared from 2-fluoro-3-nitropyridine and 2-iodophenolfollowing the same procedure as for Example A166. (M+H)⁺═463.9.

Example A1693-(5-(2-(2-tert-butylphenoxy)pyridin-3-ylamino)-1,3,4-thiadiazol-2-yl)phenol

Example A169 was prepared according to the procedure described forExample 1. (M+H)⁺═419.

Example A170N-(5-Phenyl-1,3,4-thiadiazol-2-yl)-2-(1,2,3,4-tetrahydroquinolin-5-yloxy)pyridin-3-amine

Example Al 70a 1-Benzoyl-1,2,3,4-tetrahydroquinolin-5-yl benzoate

A mixture of quinolin-5-ol (540 mg, 3.72 mMol), 10% palladium oncharcoal (Degussa 50% wet, 100 mg) were diluted in ethyl acetate andhydrogenated under 1 atmosphere of hydrogen for 18 h. The mixture wasfiltered over Celite® and evaporated in vacuo. The crude material wasdiluted in dichloromethane. Benzoyl chloride (906 gl, 7.8 mMol) anddiisopropylethylamine (1.97 mL, 11.2 mMol) were added and mixture wasstirred at rt for 3 h. The mixture was dissolved in EtOAc, washed with asaturated solution of ammonium chloride and a IN HCl solution, dried(MgSO₄), filtered and evaporated to afford the crude product (1.31 g).(M+H)⁺═358.

Example A170b (5-Hydroxy-3,4-dihydroquinolin-1(2H)-yl)(phenyl)methanone

Example A170a (1.31 g, 3.66 mMol) is diluted in THF (20 mL). A solutionof lithium hydroxide monohydrate (769 mg, 18.3 mMol) in water (10 mL)was added and mixture was stirred for 18 h. The mixture was dissolved inEtOAc, washed with a saturated solution of sodium bicarbonate, dried(MgSO₄), filtered and evaporated to afford the crude product (560 mg).(M+H)⁺═254.

Example A170c(5-(3-Nitropyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)(phenyl)methanone

A mixture of Example A170b (560 mg, 2.21 mMol), 2-chloro-2-nitropyridine(525 mg, 3.31 mMol) and cesium carbonate (1.08 g, 3.31 mMol) in DMF (10mL) was stirred at rt for 18 h. Water (25 mL) was added and mixture wasextracted twice using ethyl acetate. The organic phases was dried(MgSO₄), filtered and evaporated to afford the crude product (800 mg).(M+H)⁺═376.

Example A170d(5-(3-Aminopyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)(phenyl)methanone

A mixture of Example A170c (800 mg, 2.13 mMol), zinc (697 mg, 10.7 mMol)and ammonium chloride (572 mg, 10.7 mMol) in ethanol (20 mL) was heatedto reflux for 24 h. The solution was filtered over a pad of Celite® andevaporated in vacuo to afford the crude final product. The crudematerial was directly used in the next step. (M+H)⁺═346.

Example A170ePhenyl(5-(3-(5-phenyl-1,3,4-thiadiazol-2-ylamino)pyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)methanone

A mixture of Example A170d (400 mg, 1.16 mMol),1,1′-thiocarbonyldi-2(1H)-pyridone (269 mg, 1.16 mMol) in DCM (10 mL)was agitated at rt for 4 h. The mixture was evaporated and diluted inTHF (5 mL), benzohydrazide (79 mg, 0.58 mMol) was added and mixture wasstirred for 18 h. The solution was evaporated in vacuo and diluted insulfuric acid (conc. 5 mL) and stirred 2 h. Water was added and thesolid formed was collected by filtration and purified using preparativeHPLC to afford the final product ( 110 mg ). (M+H)⁺═506.

Example A170

Example A170e ( 100 mg, 0.2 mMol) was diluted in THF (5 mL) and cooledto −78° C. Butyllithium (1.6 M/hexanes, 0.63 mL, 1 mMol) was added andthe reaction mixture was stirred for 30 min. A saturated solution ofammonium chloride was added. The solution was warmed to r.t. andextracted twice using ethyl acetate. Organic phase were combined, dried(MgSO₄) and evaporated. The crude material was directly purified usingpreparative HPLC to afford the final product as 2 TFA salt (100 mg).(M+H)⁺═402. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.70-1.79 (mn, 2 H) 2.07 (s,1 H) 2.44 (t, J═6.32 Hz, 3 H) 3.13-3.20 (m, 2 H) 6.42 (d, J═5.31 Hz, 1H) 6.50 (d, J═7.07 Hz, 1 H) 6.99 (t, J═7.83 Hz, 1 H) 7.12 (dd, J═7.83,4.80 Hz, 1 H) 7.48 -7.55 (m, 3 H) 7.67 (dd, J═4.93, 1.64 Hz, 1 H) 7.87(dd, J═7.45, 2.15 Hz, 2 H) 8.86 (dd, J═7.96, 1.64 Hz, 1 H) 10.50 (s, 1H).

Example A171N-(5-phenyl-1,3,4-thiadiazol-2-yl)-2-(1,2,3,4-tetrahydroquinolin-8-yloxy)pyridin-3-amine

The 3-amino-phenoxypyridyl intermediate((8-(3-aminopyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)(phenyl)methanone) leading to Example A171 was made according tothe sequence described in Scheme 13 in U.S. patent application Ser. No.11/126,915, which is hereby incorporated by reference.

Example A172N-(3-tert-Butyl-1,2,4-thiadiazol-5-yl)-2-(1,2,3,4-tetrahydroquinolin-5-yloxy)pyridin-3-amine

Example A172a(5-(3-(3-tert-butyl-1,2,4-thiadiazol-5-ylamino)pyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)(phenyl)methanone

A mixture of(5-(3-aminopyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)(phenyl)methanone(Example A171d) (224 mg, 0.58 mMol), 1,1′-thiocarbonyldi-2(1H)-pyridone(269 mg, 1.16 mMol) in DCM (10 mL) was agitated at rt for 4 h. Themixture was evaporated and diluted in THF (5 mL), pivalamidine (79 mg,0.58 mMol) and DIPEA (205 gl, 1.16 mMol) were added and mixture washeated at 80° C. in a sealed tube for 24 h. The solution was cooled downand DEAD (183 gl, 1.16 mMol) was added, mixture was stirred for 2 h. Thereaction mixture was evaporated in vacuo and purified using preparativeHPLC to afford the final product ( 40 mg ). (M+H)⁺=486.

Example A172

Example A172a ( 35 mg, 0.06 mMol) was diluted in THF (5 mL) and cooledto −78° C. Butyllithium (1.6 M/hexanes, 0.19 mL, 0.3 mMol) was added andthe reaction mixture was stirred for 30 min. A saturated solution ofammonium chloride was added. The solution was warmed to rt and extractedtwice using ethyl acetate. Organic phase were combined, dried (MgSO₄)and evaporated. The crude material was directly purified usingpreparative HPLC to afford the final product as 2 TFA salt (4 mg).(M+H)⁺═382. ¹H NMR (400 MHz, DMSO-D₆) δ ppm 1.35 (s, 9 H) 1.66-1.75 (m,2 H) 2.39 (t, J═6.06 Hz, 2 H) 3.13 (s, 2 H) 6.28 (dd, J═7.71, 5.18 Hz, 1H) 6.34-6.44 (m, 1 H) 6.88-6.95 (m, 1 H) 7.13 (dd, J═7.83, 4.80 Hz, 1 H)7.68 (dd, J═4.93, 1.64 Hz, 1 H) 8.87 (dd, J═7.83, 1.52 Hz, 1 H) 10.76(s, 1 H).

Example A173N-(3-tert-Butyl-1,2,4-thiadiazol-5-yl)-2-(1,2,3,4-tetrahydroquinolin-8-yloxy)pyridin-3-amine

The 3-amino-phenoxypyridyl intermediate((8-(3-aminopyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)(phenyl)methanone) leading to Example A173 was made according tothe sequence described in Scheme 13 in U.S. patent application Ser. No.11/126,915, which is hereby incorporated by reference.

Example A174 Methyl2-(3-(3-tert-butyl-1,2,4-thiadiazol-5-ylamino)pyridin-2-yloxy)benzoate

Example A174a Methyl 2-(3-aminopyridin-2-yloxy)benzoate

Example A174a was prepared according to the procedures described in U.S.patent application Ser. No. 11/126,915, which is hereby incorporated byreference, using methyl salicylate and 2-chloro-3-nitro pyridine in thefirst step. (M+H)⁺═245.

Example A174

A mixture of Example A174a (163 mg, 0.66 mMol), diisopropylethylamine(219 gl, 1.25 mMol) and tert-butyl amidine (86 mg, 0.63 mmol) in DMF(2.1 mL) was stirred at rt for 18 h. Diethylazodicarboxylate (196 gl,1.25 mMol) was added and mixture was stirred for 4 h. The reactionmixture was purified by preparative HPLC to give the title compound (152mg) as a white solid. (M+H)⁺═385. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.36(s, 9 H) 3.53 (s, 3 H) 7.13 (dd, J═7.96, 4.93 Hz, 1 H) 7.35 (d, J═8.08Hz, 1 H) 7.40 (t, J═7.20 Hz, 1 H) 7.61 (dd, J═4.80, 1.52 Hz, 1 H) 7.70(td, J═7.77, 1.64 Hz, 1 H) 7.92 (dd, J═7.83, 1.52 Hz, 1 H) 8.91 (dd,J═8.08, 1.52 Hz, 1 H) 10.77 (s, 1 H).

Example A1752-(3-tert-Butyl-2-ethylisoindolin-4-yloxy)-N-(S-methyl-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example A175a N-Ethyl-3-methoxybenzamide

To a solution of 3-methoxybenzoyl chloride (commercially available fromAldrich, 5 mL, 35 mol) and Et₃N (10 mL) in 100 mL of DCM was added andEtNH₂ (2 M/THF, 30 mL, 60 mMol) dropwise for 30 min at 0° C. and theresulting solution was stirred for additional 1 H. The reaction mixturewas washed with aq. NaHCO₃ and brine, consecutively. The organic layerwas dried over Na₂SO₄ and concentrated in vacuo, yielding oily residue,which was subjected to column chromatography to yield Example A175a (6.2g, >95%) as a colorless oil.

Example A175b (3-tert-Butyl-2-ethyl-3-hydroxy-4-methoxyisoindolin-1-one)

Example A175a (6.1 g, 34 mMol) in THF (200 mL) was stirred at 0° C.n-Butyllithium (1.6 M in hexanes, 50 mL, 80 mMol) was added dropwise for1 H and the mixture was stirred for 2 h. Trimethylacetylchloride (4.5mL, 36 mMol) was added and stirring was continued for 1 h. A saturatedsolution of ammonium chloride was added and the solution was warmed tort and extracted twice using ethyl acetate (150 mL×2). Organic phaseswere combined, dried using MgSO₄ and evaporated. The oily mixture waspurified on column chromatography (0-100% EtOAc/Hexane) to yield 5.1 g(19.4 mMol, 57%) of Example A175b as an oil.

Example A175c (3-tert-Butyl-2-ethyl-4-methoxyisoindolin-1-one)

To a solution of Example A175b (5.1 g, 19.4 mMol) in a solution of TFA(20 mL) and DCM (20 ml) was added Et₃SiH (6.5 mL, 42 mMol) dropwise for30 min. The resulting solution was stirred for 12 h at 25° C. It wasthen concentrated in vacuo, yielding oily residue, which was dilutedwith DCM (150 ml) and washed with aq. NaHCO₃ (30 mL×2). The organiclayer was dried over MgSO₄ and concentrated to provide oily residue,which was purified on column chromatography (0-100% ethyl acetate,hexane) to yield 2.7 g (10.9 mMol, 56%) of Example A175c.

Example A175d (3-tert-Butyl-2-ethyl-4-hydroxyisoindolin-1-one)

To a solution of Example A175c (2.7 g, 10.9 mMol) in DCM (30 mL) wasadded BBr₃ (20 mL, 1M in DCM) dropwise for 0.5 h and the resultingsolution was stirred for 0° C. for 12 h. The mixture was then cooleddown to −78° C. and 5 mL of MeOH was added into the solution. Theresulting solution was stirred for additional 2 h at 25° C. It wasconcentrated in vacuo to provide Example A175d as a dark brown oil,which was subjected to following reaction without further purification.

Example A175d (3-tert-Butyl-2-ethylisoindolin-4-ol)

A mixture of Example A175d (2.5 g, 10.7 mMol) and lithium aluminiumhydride (20 mL, 1 M in THF, 20 mMol) in 100 mL of THF was stirred atreflux for 18 h. The reaction mixture was cooled down and Sodium sulfatedecahydrate was added. The mixture was stirred for 30 min. The reactionmixture was filtered over a pad of Celite® and washed with ethylacetate.The organic phase was concentrated in vacuo to provide Example A175d asan oil (2.3 g, >95%), which was identified by ¹H NMR and subjected tothe following reaction without further purification.

Example A175e(1-tert-Butyl-2-ethyl-7-(3-nitropyridin-2-yloxy)isoindoline)

A mixture of Example A175d (2.5 g, 10.7 mMol), 2-chloro-2-nitropyridine(2.4 g, 16.0 mMol) and cesium carbonate (10 g, 32.1 mMol) in DMF (30 mL)was stirred at 60° C. for 2 h. The mixture directly purified on columnchromatography (0-100%, EtOAc/hexane) to give Example A175e (2.6 g, 7.6mmol).

Example A175g(2-(3-tert-Butyl-2-ethylisoindolin-4-yloxy)pyridin-3-amine)

A mixture of Example A175e (2.6 g, 7.6 mMol), zinc (6.5 g, 100 mmol) andammonium chloride (5.4 g, 100 mMol) in ethanol (100 mL) was heated toreflux for 24 h. The solution was allowed to cool and filtered over apad of Celite and evaporated in vacuo. The crude material was purifiedusing column chromatography (0-10%, methanol, dichloromethane) to giveExample A175g (1.3 g, 4.1 mMol).

Example A175h(1-Benzoyl-3-(2-(3-tert-butyl-2-ethylisoindolin-4-yloxy)pyridin-3-yl)thiourea)

Example A175g (145 mg, 0.466 mMol) was dissolved in 5 mL ofdichloromethane. Benzoylisothiocyanate (75 gl, 0.559 mMol) was added andthe mixture was heated to 40° C. for 2 h. The reaction mixture wascooled and purified on flash chromatography (20 g SiO₂; column packedwith hexane saturated with ammonia then eluted with dichloromethane) toprovide 167 mg (76%) of Example A175h as a yellow oil. HPLC; LC/MS; ¹HNMR (400 MHz, CDCl₃).

Example A175i(1-(2-(3-tert-Butyl-2-ethylisoindolin-4-yloxy)pyridin-3-yl)thiourea)

Example A175h (155 mg, 0.327 mMol) was dissolved in 4 mL of 50% methanoland 50% tetrahydrofuran. Lithium hydroxide (2.0 M aq, 0.327 mL, 0.653mmol) was added and the mixture was heated to 50° C. for 3 h. Thereaction mixture was purified by flash chromatography (20 g SiO₂; columnpacked with 2% of 7 M ammonia in methanol and dichloromethane theneluted with 2% methanol in dichloromethane) to provide 99 mg (82%) ofExample A175i as an orange solid.

Example A175

Example A175i (46 mg, 0.124 mMol) and 1,1,1-trifluoro-3-bromo-2-butanone(51 mg, 0.248 mMol, commercially available) were dissolved in 1 mL ofethanol. 2,6-Lutidine (29 gl, 0.248 mMol) was added and the mixture washeated to 100° C. for 4 h in a sealed tube. The reaction mixture wascooled to room temperature and the solvent removed. The residue waspurified by flash chromatography (15 g SiO₂; eluted with 3% i-propanol,dichloromethane) to provide Example A175 that was only 88% pure. Furtherpurification by preparative thin layer chromatrography (plate elutedwith 3% i-propanol, dichloromethane) provided 22 mg (37%) of pureExample A175. HPLC, LC/MS, ¹H NMR (400 MHz, CDCl₃), MS (ESI) 477 (M+H).HRMS (ESI) m/e calc'd for C₂₄H₂₈F₃N₄OS: 477.1936. Found (M+): 477.1927.

Example A1762-(3-tert-Butyl-2-ethylisoindolin-4-yloxy)-N-(5-phenyl-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example A176a (3-bromo-1,1,1-trifluoro-3-phenylpropan-2-one)

1,1,1-trifluoro-3-phenylpropanone (0.50 mL, 3.2 mMol) was dissolved in 5mL of diethyl ether and the mixture was cooled to 0° C. Bromine (0.16mL, 3.2 mmoL) was added and the mixture was stirred for 18 h and allowedto warm to rt. The solvent was removed to provide a 2:1 mixture ofExample A176a as a starting material which was used in the subsequentreaction without further purification.

Example A176

Example A175i (43 mg, 0.124 mMol) and Example A176a (124 mg) weredissolved in 1 mL of ethanol. Pyridine (19 gl, 0.232 mMol) was added andthe mixture was heated to 100° C. for 3 h in a sealed tube. The reactionmixture was cooled to rt and the solvent was removed. The residue waspurified by preparative thin layer chromatrography (plate eluted with 5%i-propanol, dichloromethane) to provide 14 mg (22%) of Example A176.HPLC, LC/MS, ¹H NMR (400 MHz, CDCl₃), MS (ESI) m/e 539 (M+H); HRMS (ESI)m/e calc'd for C₂₉H₃₀F₃N₄OS: 539.2092. Found (M+): 539.2085.

Example A1772-(2-Neopentyl-1,2,3,4-tetrahydroisoquinolin-5-yloxy)-N-(5-phenyl-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example A177a(1-(5-Amino-3,4-dihydroisoquinolin-2(1H)-yl)-2,2-dimethylpropan-1-one)

1,2,3,4-tetrahydroisoquinolin-5-amine (commercially available fromAldrich, 1 g, 6.7 mMol) was dissolved in 20 mL of dichloromethane.1,1-dimethlypropanoic acid (0.68 g, 6.7 mMol) and EDC (1.28 g, 6.7vnuol) were added and the mixture was stirred for 6 h at rt. The solventwas removed and the residue purified by flash chromatography (SiO₂;0-100% ethyl acetate hexane) to provide 0.48 g (31%) of Example A177a asa yellow oil. HPLC; ¹H NMR (400 MHz, CDCl₃).

Example A177b(1-(5-Hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-2,2-dimethylpropan-1-one)

Example A177a (0.48 g, 2.1 mMol) was dissolved in 25 mL of 15% sulfuricacid. The reaction mixture was stirred at 60° C. for 0.5 h and NaNO₂(0.15 g, 2.1 mMol) in 4 mL of H₂O was added dropwise. The reactionmixture was stirred at 60° C. for additional 1 h, then cooled to 25° C.The aqueous layer was extracted with EtOAc (40 mL×2). The organicsolution was dried over sodium sulfate and concentrated in vacuo,yielding oily residue which was purified on column chromatography(0-100% ethyl acetate, hexane) to provide 0.27 g (1.15 mMol, 55%) ofExample A177b.

Example A177c (2-Neopentyl-1,2,3,4-tetrahydroisoquinolin-5-ol)

Example A177b (0.27 g, 1.15 mmol) was dissolved in 10 mL of THF. Lithiumaluminum hydride (1.0 M in THF, 5 mL, 5 mMol) was added an the mixturewas heated to 50° C. for 6 h. The reaction was cooled and quenched witha few drops of water. The reaction mixture was filtered and the solventremoved. The residue was purified by flash chromatography (ISCO system40 g SiO₂; eluted with 0-100% ethyl acetate, hexane) to provide 0.26 g(>95%) of Example A177c as a yellow oil. HPLC; ¹H NMR (400 MHz, CDCl₃).

Example A177d(2-Neopentyl-5-(3-nitropyridin-2-yloxy)-1,2,3,4-tetrahydroisoquinoline)

Example A177c (260 mg, 1.2 mMol) and 2-chloro-3-nitrobenzene (225 mg,1.4 mMol) were heated to 60° C. for 3 h. The mixture was cooled and themixture was purified by flash chromatography (ISCO system 40 g SiO₂;eluted with 0-100% ethyl acetate hexane) to provide 170 g (41%) ofExample A177d as a yellow oil. HPLC; ¹H NMR (400 MHz, CDCl₃).

Example A177e(2-(2-Neopentyl-1,2,3,4-tetrahydroisoquinolin-5-yloxy)pyridin-3-amine)

Example A177d was dissolved in 5 mL of methanol. Palladium (5% oncharcoal, 20 mg) was added and the mixture was stirred for 12 h at rtunder 1 μm hydrogen. The mixture was purged with nitrogen then filteredthrough Celite®. The solvent was removed to provide Example A177e whichwas subjected to the subsequent reaction without further purification(150 mg, >95%). HPLC; ¹H NMR (400 MHz, CDCl₃).

Example A177f(1-Benzoyl-3-(2-(2-neopentyl-1,2,3,4-tetrahydroisoquinolin-5-yloxy)pyridin-3-yl)thiourea)

Example A177e (50 mg, 0.16 mMol) was dissolved in 2 mL ofdichloromethane. Benzoylisothiocyanate (26 RL, 0.19 mMol) was added andthe mixture was heated to 40° C. for 6 h. The reaction mixture wascooled and the solvent removed to provide Example A177f (LC/MS 475 M+H)as a brown oil that was used in the subsequent reaction withoutpurification or further characterization.

Example A177g(1-(2-(2-Neopentyl-1,2,3,4-tetrahydroisoquinolin-5-yloxy)pyridin-3-yl)thiourea)

Example Al 77f was dissolved in 2 mL of 50% methanol and 50%tetrahydrofuran. Lithium hydroxide (2.0 M aq, 0.16 mL, 0.32 mMol) wasadded and the mixture was heated to 50° C. for 3 h. The reaction mixturewas concentrated then partitioned between water and ethyl acetate. Theaqueous phase was extracted with ethyl acetate. The combined organicextracts were dried over magnesium sulfate, filtered and the solventremoved to provide 65 mg of a brown oil. The residue was purified byflash chromatography (15 g SiO₂; eluted with 5% methanol, 25% ethylacetate, hexane) to provide 35 mg of a yellow oil that contained thedesired product with some impurities. Repurification using the sameflash chromatography conditions provided 18 mg (30% over 2 steps) ofpure Example A177g. HPLC; ¹H NMR(400 MHz, CDCl₃).

Example A177

Example A177g (18 mg, 0.049 mMol) and Example 176a (43 mg) weredissolved in 0.5 mL of ethanol. Pyridine (8 gl, 0.1 mMol) was added andthe mixture was heated to 100° C. for 1.5 h in a sealed tube. Thereaction mixture was cooled to rt and the solvent removed. The residuewas purified by preparative HPLC (YMC Pack ODS-A 5μ, 30 mM×100 mMcolumn, eluted with 42-90% methanol and water with 0.1% TFA, lineargradient over 10 min, 40 mL/min) to provide 20 mg (77%) of the TFA saltof compound J(2-(2-neopentyl-1,2,3,4-tetrahydroisoquinolin-5-yloxy)-N-(5-phenyl-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine)as a tan powder. HPLC, LC/MS, ¹H NMR (400 MHz, CDCl₃), MS (ESI) m/e 539(M+H); HRMS (ESI) m/e calc'd for C₂₉H₃₀F₃N₄OS: 539.2092. Found (M⁺):539.2081.

Example A1782-(2-(1-Neopentylpiperidin-4-yl)phenoxy)-N-(5-phenyl-4-(trifluoromethyl)thiazol-2-yl)pyridin-3-amine

Example A178a 2-(Piperidin-4-yl)phenol

A solution of 4-(2-methoxyphenyl)piperidine (Fluka, 5 g, 26.1 mMol) in48% hydrobromic acid (45 mL) was heated to 100° C. for 3 days. Themixture was then allowed to cool down to rt and it was concentratedunder reduced pressure to give 2-(piperidin-4-yl)phenol as a light pinksolid which was used directly in the next step. M+H═178.1.

Example A178b 2-(I-Neopentylpiperidin-4-yl)phenol

Example A178b was made from Example A178a using the reductive aminationprocedure previously described. The crude product was used directlywithout further purification. M+H═248.2.

Example A178c 2-(2-(1-Neopentylpiperidin-4-yl)phenoxy)-3-nitropyridine

Example A178c was made from Example A178b using the standard proceduredescribed above. M+H═370.2.

Example A178d 2-(2-(1-Neopentylpiperidin-4-yl)phenoxy)pyridin-3-amine

Example A178d was made from the reaction of zinc dust, ammonium chlorideand Example A178c as described above. M+H═340.2.

Example A178

Example A178 was prepared from Example A178a using the similar proceduredescribed for Example 217. (M+H)⁺═567.0. ¹H nmr (400 MHz, MeOH-d₄) δppm8.95 (m, 1H), 7.65-7.07 (m, 1 H), 3.67 (mn, 2H), 3.15 (m, 3H), 2.99 (s,2H), 2.13 (m, 4H), 1.11 (s, 9H).

Utility

The compounds of the present invention are anti-platelet agents and thusare useful to maintain the fluidity of blood. Additionally, compounds ofthe present invention are useful for the treatment or prophylaxis ofplatelet-associated disorders. As used herein, the term“platelet-associated disorder” refers to any disorder which may beprevented, partially alleviated or cured by the administration of ananti-platelet agent. Thus, the compounds of the present invention areuseful in the treatment or prevention of various platelet associateddisorders including: thrombotic or thromboembolic conditions; acutecoronary syndromes (such as coronary artery disease, myocardialinfarction (MI), unstable angina and non-Q Wave MI); thromboembolicstroke (such as that resulting from atrial fibrillation or fromventricular mural thrombus (low ejection fraction)); venous thrombosis(including deep vein thrombosis); arterial thrombosis; cerebralthrombosis; pulmonary embolism; cerebral embolism; kidney embolisms;peripheral occlusive arterial disease (e.g., peripheral arterialdisease, intermittent claudication, critical leg ischemia, prevention ofamputation, prevention of cardiovascular morbidity such as MI, transientischemic attack, stroke or ischemic sudden death); thromboembolicconsequenses of surgery, interventional cardiology or immobility;thromboembolic consequenses of medication (such as oral contraceptives,hormone replacement and heparin); thrombotic consequenses ofatherosclerotic vascular disease and atherosclerotic plaque ruptureleading to tissue ischemia; prevention of atherosclerotic plaqueformation; transplant atherosclerosis; thromboembolic complications ofpregnancy including fetal loss; thromboembolic consequences ofthrombophilia (e.g., Factor V Leiden, and homocystinenimia);prothrombotic consequences and/or complications of cancer; prevention ofthrombosis on artificial surfaces (such as stents, blood oxygenators,shunts, vascular access ports, vascular grafts, artificial valves,etc.); coagulopathies (e.g., disseminated intravascular coagulation(DIC)); coagulation syndromes; vascular remodeling atherosclerosis,restenosis and systemic infection; prevention of metastesis and tumorimplantation; diabetic complications including retinopathy, nephropathyand neuropathy; inflammation (e.g., thrombophlebitis); ischemia (such asthat resulting from vascular occlusion, cerebral infarction, transientischemic attack, stroke and related cerebral vascular diseases);Kasabach-Merritt syndrome; atrial fibrillation; ventricular enlargement(including dilated cardiac myopathy and heart failure); restenosis(e.g., following arterial injury- induced either endogenously orexogenously); thrombosis resulting from medical implants, devices, orprocedures in which blood is exposed to an artificial surface thatpromotes thrombosis. The medical implants or devices include, but notlimited to: prosthetic valves, indwelling catheters, stents, and vesselgrafts. The procedures include, but not limited to: cardiopulmonarybypass and hemodialysis.

In general, a thromboembolic disorder is a circulatory disease caused byblood clots (i.e., diseases involving fibrin formation, plateletactivation, and/or platelet aggregation). The term “thromboembolicdisorders” as used herein also includes arterial or venouscardiovascular or cerebovascular thromboembolic disorders, andthromboembolic disorders in the chambers of the heart.

In addition to acting as anti-platelet agents, the compounds of thepresent invention may also find utility in a variety of other settingsincluding as inhibitors of bone resorption such as encountered invarious osteoporotic conditions, as inhibitors of insulin secretion inconditions of hyperinsulinemia, as vasoconstrictive agents such as thoseused in cases of septic or hypovolemic shock, as inhibitors of smoothmuscle relaxation such for the treatment of incontinence or in othercases where inhibition of sympathetic never transmission would be oftherapeutic benefit such as nociception or neuronal tissue regeneration.These and many other potential utilities for P2Y₁ antagonists have beenrecently reviewed (Burnstock, G. and Williams, M. J. Pharm. Exp Ther.2000, 295, 862-9) and are suggested therein.

Compounds of the present invention may additionally be useful asdiagnostic agents and adjuncts. For example, the present compounds maybe useful in maintaining the reactivity of fractionated whole bloodcontaining platelets such as required for analytical and biologicaltesting or transfusions. In addition, the compounds of the presentinvention may be useful for maintaining blood vessel patency inconjunction with vascular surgery including bypass grafting, arterialreconstruction, atherectomy, vascular graft and stent patency, organ,tissue and cell implantation and transplantation. In addition, thecompounds of the present invention may be useful for maintaining bloodvessel patency in conjunction with interventional cardiology or vascularsurgery including bypass grafting, arterial reconstruction, atherectomy,vascular graft and stent patency, organ, tissue and cell implantationand transplantation.

P2Y₁ Assays

A. Binding Assay

A membrane binding assay was used to identify inhibitors of [³³P]2MeS-ADP binding to cloned human P2Y₁ receptors. The cDNA clone forhuman P2Y₁ was obtained from Incyte Pharmaceuticals and its sequenceconfirmed by established techniques (for a compendium of techniques usedsee Ausubel, F. et al. Current Protocols in Molecular Biology 1995 JohnWiley and Sons, NY, N.Y.). The essential coding sequences were subclonedinto pCDNA 3.1 (Invitrogen) to produce a P2Y₁ expression construct. Thisconstruct was then transfected into the human embryonic kidney cell lineHEK-293 and stable transfectants selected in Genetcin® (G418 sulfate;Life Technologies). Several lines were screened for binding activity andone (HEK293 #49) selected for further characterization. Membranes wereprepared by growing HEK293 #49 in 150 mM dishes in DMEM/10% FBS in thepresence of I mg/ml G418 until cells were 80-90% confluent. Plates werethen washed with cold (4° C.) D-PBS twice and cells harvested byscraping into 10 mL D-PBS. Cells were pelleted by centrifugation (1,000g, 10 min, 4° C.) and the resulting pellet resuspended in Lysis Buffer(10 mM Tris (7.4), 5 mM MgCl₂ containing Complete protease inhibitorcocktail (Roche Cat #1873580) as recommended by the manufacturer). Thesuspension was then homogenized in a Dounce homogenizer (10-15 strokes;B pestle, on ice) and the homogenate spun at 1,000 g, 4° C., 5 min topellet large debris. The supernatant was centrifuged at 150,000g, 4° C.,for 1 hour and the resulting membrane pellet resuspended in 0.5-1 mL ofBuffer B (15 mM HEPES (7.4), 145 mM NaCl, 0.1 mM MgCL₂, 5 mM EDTA, 5 mMKCI) and stored at −70° C. until used.

Binding reactions were performed in WGA FlashPlates (PerkinElmer LifeSciences, Cat # SMP105A) in a volume of 200 gl containing ˜45 finol ofP2Y₁ receptor (5 μg of total protein), 0.5 nM [³³P] 2MeS-ADP(PerkinElmer; 2,000 Ci/mmol), and various concentrations of the testcompound (usually between 50 μM and 10 pM) in Buffer B containing 1%DMSO. Reactions were allowed to proceed to completion at roomtemperature for 1 hour and then the aqueous solution aspirated. Plateswere sealed and the residual [33P] bound to the plate determined byscintillation counting. Dose-response curves (IC₅₀) were fit bynon-linear regression (XLFit, ID Business Solutions Ltd.) and bindingconstants (K_(i)) calculated using the Cheng- Prusoff relationship(K_(i)═IC₅₀/(1+L/K_(d)) in which a K_(d) for 2MeS-ADP to the P2Y₁receptor was determined to be 1.4 nM.

Compounds tested in the P2Y₁ binding assay are considered to be activeif they exhibit a K_(i) of equal to or less than 10 μM. Preferredcompounds of the present invention have K_(i)'s of equal to or less than1 μM. More preferred compounds of the present invention have K_(i)'s ofequal to or less than 0.1 μM. Even more preferred compounds of thepresent invention have K_(i)'s of equal to or less than 0.01 μM.Compounds of the present invention have demonstrated K_(i) values ofequal to or less than 10 μM in the assay for P2Y₁ binding, therebyconfirming that they act to modulate P2Y₁ activity.

The compounds of the present invention may be used in combination witheach other, or with other anti-platelet agents. Additionally, thepresent compounds may be used in combination with one or more of variousother therapeutic agents, including: anti-arrythmic agents;anti-hypertensive agents;, anti-thrombotic and/or anti-thrombolyticagents; calcium channel blockers (L-type and T-type); cardiacglycosides; diruetics, mineralocorticoid receptor antagonists;phospodiesterase inhibitors; cholesterol/lipid lowering agents and lipidprofile therapies; anti-diabetic agents; anti-depressants;anti-inflammatory agents (steroidal and non-steroidal);anti-osteoporosis agents; hormone replacement therapies; oralcontraceptives; anti-coagulants; anti-obesity agents; anti-anxietyagents; anti-proliferative agents; anti-tumor agents; anti-ulcer andgastroesophageal reflux disease agents; growth hormone and/or growthhormone secretagogues; thyroid mimetics (including thyroid receptorantagonist); anti-infective agents; anti-viral agents; anti-bacterialagents; and anti-fungal agents.

Examples of suitable anti-arrhythmic agents for use in combination withthe present compounds include: Class I agents (such as propafenone);Class II agents (such as carvadiol and propranolol); Class III agents(such as sotalol, dofetilide, amiodarone, azimilide and ibutilide);Class IV agents (such as ditiazem and verapamil); K⁺ channel openerssuch as I_(Ach) inhibitors, and I_(Kur) inhibitors (e.g., compounds suchas those disclosed in U.S. Application Publication US 20030022890.

Examples of suitable anti-hypertensive agents for use in combinationwith the compounds of the present invention include: alpha adrenergicblockers; beta adrenergic blockers; calcium channel blockers (e.g.diltiazem, verapamil, nifedipine, amlodipine and mybefradil); diruetics(e.g., chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzthiazide, ethacrynic acidtricrynafen, chlorthalidone, furosemide, musolimine, bumetanide,triamtrenene, amiloride, spironolactone); renin inhibitors; ACEinhibitors (e.g., captopril, zofenopril, fosinopril, enalapril,ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril,lisinopril); AT-1 receptor antagonists (e.g., losartan, irbesartan,valsartan); ET receptor antagonists (e.g., sitaxsentan, atrsentan andcompounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265); DualET/AII antagonist (e.g., compounds disclosed in WO 00/01389); neutralendopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACEinhibitors) (e.g., omapatrilat, gemopatrilat and nitrates).

Examples of suitable anti-platelet agents for use in combination withthe compounds of the present invention include: GPIlb/IIIa blockers(e.g., abciximab, eptifibatide, tirofiban, integrelin); other P2Y₁₂antagonists (e.g., clopidogrel, ticlopidine, Prasugrel); thromboxanereceptor antagonists (e.g., ifetroban); aspirin; and PDE-III inhibitors(e.g., dipyridamole) with or without aspirin.

Examples of suitable anti-thrombotic and/or anti-thrombolytic agents foruse in combination with the compounds of the present invention include:tissue plasminogen activator (natural or recombinant), tenecteplase(TNK), and lanoteplase (nPA); factor VIIa inhibitors; factor Xainhibitors; factor XIa inhibitors; thrombin inhibitors (such as hirudinand argatroban); PAI-I inhibitors (i.e., inactivators of tissueplasminogen activator inhibitors); alpha2-antiplasmin inhibitors;streptokinase, urokinase and prourokinase; and anisoylated plasminogenstreptokinase activator complex.

Examples of suitable calcium channel blockers (L-type or T-type) for usein combination with the compounds of the present invention includediltiazem, verapamil, nifedipine, amlodipine and mybefradil.

Examples of suitable cardiac glycosides for use in combination with thecompounds of the present invention include digitalis and ouabain.

Examples of suitable diruetics for use in combination with the compoundsof the present invention include: chlorothiazide, hydrochlorothiazide,flumethiazide, hydroflumethiazide, bendroflumethiazide,methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide,ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine,bumetanide, triamtrenene, amiloride, and spironolactone.

Examples of suitable mineralocorticoid receptor antagonists for use incombination with the compounds of the present invention includesprionolactone and eplirinone.

Examples of suitable phospodiesterase inhibitors for use in combinationwith the compounds of the present invention include: PDE III inhibitors(such as cilostazol); and PDE V inhibitors (such as sildenafil).

Examples of suitable cholesterol/lipid lowering agents and lipid profiletherapies for use in combination with the compounds of the presentinvention include: HMG-CoA reductase inhibitors (e.g., pravastatinlovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, ornisvastatin or nisbastatin) and ZD-4522 (a.k.a. rosuvastatin, oratavastatin or visastatin)); squalene synthetase inhibitors; fibrates;bile acid sequestrants (such as questran); ACAT inhibitors; MTPinhibitors; lipooxygenase inhibitors; choesterol absorption inhibitors;and cholesterol ester transfer protein inhibitors (e.g., CP-529414).

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include: biguanides (e.g.metformin); glucosidase inhibitors (e.g. acarbose); insulins (includinginsulin secretagogues or insulin sensitizers); meglitinides (e.g.repaglinide); sulfonylureas (e.g., glimepiride, glyburide andglipizide); biguanide/glyburide combinations (e.g., glucovance),thiozolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone),PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dualagonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein(aP2) such as those disclosed in U.S. Pat. No. 6,548,529, glucagon-likepeptide-1 (GLP-1), and dipeptidyl peptidase IV (DP4) inhibitors.

Examples of suitable anti-depressant agents for use in combination withthe compounds of the present invention include nefazodone andsertraline.

Examples of suitable anti-inflammatory agents for use in combinationwith the compounds of the present invention include: prednisone;dexamethasone; enbrel; protien tyrosine kinase (PTK) inhibitors;cyclooxygenase inhibitors (including NSAIDs, and COX-1 and/or COX-2inhibitors); aspirin; indomethacin; ibuprofen; prioxicam; naproxen;celecoxib; and/or rofecoxib.

Examples of suitable anti-osteoporosis agents for use in combinationwith the compounds of the present invention include alendronate andraloxifene.

Examples of suitable hormone replacement therapies for use incombination with the compounds of the present invention include estrogen(e.g., congugated estrogens) and estradiol.

Examples of suitable anti-coagulants for use in combination with thecompounds of the present invention include heparins (e.g., unfractionedand low molecular weight heparins such as enoxaparin and dalteparin).

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include orlistat and aP2 inhibitors(such as those disclosed in U.S. Pat. No. 6,548,529.

Examples of suitable anti-anxiety agents for use in combination with thecompounds of the present invention include diazepam, lorazepam,buspirone, and hydroxyzine pamoate.

Examples of suitable anti-proliferative agents for use in combinationwith the compounds of the present invention include cyclosporin A,paclitaxel, adriamycin; epithilones, cisplatin, and carboplatin.

Examples of suitable anti-ulcer and gastroesophageal reflux diseaseagents for use in combination with the compounds of the presentinvention include famotidine, ranitidine, and omeprazole.

The various other therapeutic agents described above may be employed inthe same dosage form with the compound of formula I or in differentdosage forms, in dosages and regimens as generally known in the art orin the PDR.

The compounds of the present invention may act in a synergistic fashionwith one or more of the above agents to prevent reocclusion following asuccessful thrombolytic therapy and/or reduce the time to reperfusion.The compounds of the present invention may also allow for reduced dosesof the thrombolytic agent to be used and therefore minimize potentialhemorrhagic side-effects.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of platelet ADP receptor. Suchcompounds may be provided in a commercial kit, for example, for use inpharmaceutical research involving platelet ADP receptor. For example, acompound of the present invention could be used as a reference in anassay to compare its known activity to a compound with an unknownactivity. This would ensure the experimenter that the assay was beingperformed properly and provide a basis for comparison, especially if thetest compound was a derivative of the reference compound. Whendeveloping new assays or protocols, compounds according to the presentinvention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving platelet ADP receptor. For example, the presence ofP2Y₁ in an unknown sample could be determined by addition of therelevant radiolabled compound to the sample and measuring the extend ofbinding to the P2Y₁ receptor.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a thromboembolic disorder (as definedpreviously). In another embodiment, the package insert states that thepharmaceutical composition can be used in combination (as definedpreviously) with a second therapeutic agent to treat a thromboembolicdisorder. The article of manufacture can further comprise: (d) a secondcontainer, wherein components (a) and (b) are located within the secondcontainer and component (c) is located within or outside of the secondcontainer. Located within the first and second containers means that therespective container holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 1 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl-or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington 'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of the present invention and about 1 to7.5 milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 10 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 5milligrams per dosage unit.

Where the compounds of the present invention are administered incombination with an anti-platelet agent, by way of general guidance,typically a daily dosage may be about 0.01 to 25 milligrams of thecompound of the present invention and about 50 to 150 milligrams of theanti-platelet agent, preferably about 0.1 to 1 milligrams of thecompound of the present invention and about 1 to 3 milligrams ofantiplatelet agents, per kilogram of patient body weight.

Where the compounds of the present invention are administered incombination with thrombolytic agent, typically a daily dosage may beabout 0.1 to 1 milligrams of the compound of the present invention, perkilogram of patient body weight and, in the case of the thrombolyticagents, the usual dosage of the thrombolyic agent when administeredalone may be reduced by about 70-80% when administered with a compoundof the present invention.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of the present invention, generally theamount of each component in a typical daily dosage and typical dosageform may be reduced relative to the usual dosage of the agent whenadministered alone, in view of the additive or synergistic effect of thetherapeutic agents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

1. A compound of Formula (Ia):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orsolvate thereof, wherein: ring A is a 5- to 6-membered heteroarylcomprising: carbon atoms and 1-4 ring heteroatoms selected from N, NR¹¹,S(O)p, and O, wherein said heteroaryl is substituted with 0-4 R¹; ring Bis phenyl substituted with 0-4 R⁷, pyridyl substituted with 0-3 R⁷, orthienyl substituted with 0-2 R⁷; X is NH or NMe; Y is O or S; R¹ is,independently at each occurrence, F, Cl, Br, I, CF₃, —CF₂CF₃, OCF₃,—OCF₂CF₂H, —OCF₂CF₃, SiMe₃, —(CR^(f)R^(f))_(r)—OR^(c), SR^(c), CN, NO₂,—(CR^(f)R^(f))_(r)—NR¹²R¹³, —(CR^(f)R^(f))_(r)—C(O)R^(c),—(CR^(f)R^(f))_(r)—CO₂R^(c), —(CR^(f)R^(f))_(r)—C(O)NR¹²R¹³,—C(O)NR¹⁴(CR^(f)R^(f))_(t)N¹²R¹³, —(CR^(f)R^(f))_(r)—OC(O)NR¹²R¹³,—(CR^(f)R^(f))_(r)—NR¹⁴C(O)NR¹²R¹³, —(CR^(f)R^(f))_(r)—NR¹⁴C(O)R^(d),—(CR^(f)R^(f))_(r)—NR¹⁴C(O)OR^(h), —NR¹⁴(CR^(f)R^(f)),C(O)R^(d),—NR¹⁴CO(CR^(f)R^(f)),OR^(c), —(CH₂)_(r)—CR¹³(═NOR^(c)),—(CH₂)_(r)—C(NH₂)(═NOR^(c)), —S(O)_(p)NR¹²R¹³,—(CR^(f)R^(f))_(r)—NR¹⁴S(O)_(p)NR¹²R¹³, —NR¹⁴SO₂CF₃, —NR¹⁴S(O)_(p)R^(d),—S(O)₂CF₃, —S(O)R^(d), —S(O)₂R^(d), —OP(O)(OEt)₂, —O(CH₂)₂OP(O)(OEt)₂,4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl, C₁₋₈ alkyl substituted with0-2 R^(a), C₂₋₈ alkenyl substituted with 0-2 R^(a), C₂₋₈ alkynylsubstituted with 0-2 R^(a), —(CR^(f)R^(f))_(r)—C₃₋₁₃ carbocyclesubstituted with 0-5 R^(b), or —(CR^(f)R^(f))_(r)-5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, NR¹¹, O, and S(O)p, wherein said heterocycle is substituted with 0-5R^(b); alternatively, two R¹s are combined with the carbon atoms towhich they attached, form a 5- to 7-membered carbocycle or heterocyclecomprising: carbon atoms and 0-3 additional heteroatoms selected from N,NR¹¹, O, and S(O)_(p), 0-2 carbonyls, and 0-2 double bond, wherein saidcarbocycle or heterocycle is substituted with 0-4 R^(b); R⁵ is a—(CR^(f)R^(f))_(n)—C₃₋₁₀ carbocycle substituted with 1-4 R^(5a), or a—(CR^(f)R^(f))_(n)-5- to 1 0-membered heterocycle comprising: carbonatoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S(O)p, whereinsaid heterocycle is substituted with 0-4 R^(5a); R^(5a) is,independently at each occurrence, F, Cl, Br, I,—(CR^(i)R^(i))_(r)—OR^(c), SR^(c), CN, NO₂, CF₃, —CF₂CF₃, OCF₃,—OCF₂CF₂H, —OCF₂CF₃, —NR¹²R¹³, —C(O)R^(c), —C(O)OR^(c), —C(O)NR¹²R¹³,—NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³, —S(O)R^(d), —S(O)₂R^(d), —Si(Me)₃,Si(C₁₋₄ alkyl)₃, C₁₋₄ haloalkyl, C₁₋₄ haloalkyloxy-, C₁₋₄ alkyloxy-,C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(O)—, C₁₋₄ alkyl-O—C(O)—, C₁₋₄alkyl-C(O)NH—, C₁₋₈ alkyl substituted with 0-2 R^(a), C₂₋₈ alkenylsubstituted with 0-2 R^(a), C₂₋₈ alkynyl substituted with 0-2 R^(a),—(CR^(f)R^(f))_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(e), or—(CR^(f)R^(f))_(r)-5- to 10-membered heterocycle comprising: carbonatoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S(O)p, whereinsaid heterocycle is substituted with 0-3 R^(e); alternatively, twoR^(5a) groups, together with the atoms to which they are attached, forma 5- to 7-membered carbocyclic or heterocyclic ring comprising: carbonatoms and 0-2 heteroatoms selected from N, NR¹¹, O, and S(O)p, 0-1carbonyl and 0-3 double bonds, wherein said carbocyclic or heterocyclicring is substituted with 0-3 R^(e); R⁷ is, independently at eachoccurrence, H, F, Cl, Br, I, OCF₃, CF₃, OR^(c), SR^(c), CN, NO₂,—NR¹²R¹³, —C(O)R^(c), —C(O)OR^(c), —C(O)NR¹²R¹³, —NR¹⁴C(O)R^(d),—S(O)_(p)NR¹²R¹³, —S(O)R^(d), —S(O)₂R^(d), C₁₋₈ alkyl substituted with0-2 R^(a), C₂₋₈ alkenyl substituted with 0-2 R^(a), C₂₋₈ alkynylsubstituted with 0-2 R^(a), —(CR^(f)R^(f))_(r)—C₃₋₁₀ carbocyclesubstituted with 0-3 R^(b), or —(CR^(f)R^(f))_(r)-5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, NR^(7b), O, and S(O)p, wherein said heterocycle is substituted with0-3 R^(b); alternatively, two R⁷s can form a 5- to 7-memberedcarbocyclic or heterocyclic ring comprising: carbon atoms and 0-3 ringheteroatoms selected from O, N, NR^(7b), and S(O)p, wherein saidcarbocyclic or heterocyclic ring is substituted with 0-3 R⁷c; R^(7b) is,independently at each occurrence, H, C₁₋₄ alkyl, (C₁₋₄ alkyl)C(O)—,phenyl-C(O)—, benzyl-C(O)—, benzyl-S(O)₂—, (C₁₋₄ alkyl)NHC(O)—, (C₁₋₄alkyl)₂NC(O)—, phenyl-NHC(O)—, benzyl-NHC(O)—, (C₁₋₄ alkyl)-S(O)₂—,phenyl-S(O)₂—, phenyl substituted with 0-3 R^(b), or benzyl substitutedwith 0-3 R^(b); R^(7c) is, independently at each occurrence, H, F, Cl,Br, I, OCF₃, CF₃, OR^(c), SR^(c), CN, NO₂, —NR¹²R¹³, —C(O)R^(c),—C(O)OR^(c), —C(O)NR¹²R¹³, —NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³, —S(O)R^(d),—S(O)₂R^(d), C₁₋₄ alkyl, phenyl substituted with 0-3 R^(b), or benzylsubstituted with 0-3 R^(b); R¹¹ is, independently at each occurrence, H,C₁₋₆ alkyl substituted with 1-5 fluorine, —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³,C₁₋₈ alkyl substituted with 0-2 R^(a), C₂₋₈ alkenyl substituted with 0-2R^(a), C₂₋₈ alkynyl substituted with 0-2 R^(a), (C₁₋₆ alkyl)C(O)—, (C₃₋₆cycloalkyl)C₁₋₃ alkyl-C(O)—, (C₃₋₆ cycloalkyl)C(O)—, phenyl-C(O)—,benzyl-C(O)—, (C₁₋₆ alkyl)NHC(O)—, (C₁₋₆ alkyl)₂NC(O)—, phenyl-NHC(O)—,benzyl-NHC(O)—, (phenyl)(C₁₋₆ alkyl)NC(O)—, (benzyl)(C ₁₋₆ alkyl)NC(O)—,(C₁₋₆ alkyl)-S(O)2—, phenyl-S(O)2-, benzyl-S(O)₂—,—(CR^(f)R^(f))_(r)—C₃₋₁₀ carbocycle, or —(CR^(f)R^(f))_(r)-5- to10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, NR^(f), O, and S(O)_(p); wherein said phenyl, benzyl,carbocycle, and heterocycle are substituted with 0-3 R^(b); R¹² is,independently at each occurrence, H, C₁₋₆ alkyl substituted with 1-5fluorine, —(CR^(f)R^(f))_(r)C(O)NR^(f)R^(f), C₁₋₆ alkyl, (C₁₋₆alkyl)C(O)—, (C₁₋₄ alkyl)OC(O)—, (C₆₋₁₀ aryl)-CH₂—OC(O)—, (C₆₋₁₀aryl)-CH₂—C(O)—, (C₁₋₄ alkyl)-C(O)O—(C₁₋₄ alkyl)-OC(O)—, (C₆₋₁₀aryl)-C(O)O—(C₁₋₄ alkyl)-OC(O)—, (C₁₋₆ alkyl)-NHC(O)—, (C₆₋₁₀aryl)-NHC(O)—, (5- to 10-membered heteroaryl)-NHC(O)—, (5- to10-membered heteroaryl)-CH₂—OC(O)—, (5- to 10-memberedheteroaryl)-C(O)—, (C₆₋₁₀ aryl)-(C₀₋₄ alkyl)-C(O)—, (C₁₋₆ alkyl)-S(O)₂—,(C₆₋₁₀ aryl)-S(O)₂—, (5- to 10-membered heteroaryl)-S(O)₂—, or (C₆₋₁₀aryl)-(C₁₋₄ alkyl)-S(O)₂—, —(CR^(f)R^(f))_(n)—(C₆₋₁₀ aryl),—(CR^(f)R^(f))_(n)-5- to 10-membered heterocycle; wherein said alkyl,phenyl and aryl are substituted with 0-2 R^(g); said 5- to 10-memberedheteroaryl is substituted with with 0-2 R^(g) and comprises: carbonatoms and 1-4 heteroatoms selected from N, NR^(f), O, and S(O)_(p); said5- to 10-membered heterocycle is substituted with with 0-2 R^(g) andcomprises: carbon atoms and 1-4 heteroatoms selected from N, NR^(f), O,and S(O)_(p); R¹³ is, independently at each occurrence, H, C₁₋₆ alkyl,or —(CH₂)_(n)-phenyl; alternatively, R¹² and R¹³, when attached to thesame nitrogen, combine to form a 5- to 10-membered heterocyclic ringcomprising: carbon atoms and 1-2 additional heteroatoms selected from N,NR^(f), O, and S(O)_(p); R¹⁴ is, independently at each occurrence, H,C₁₋₆ alkyl substituted with 0-2 R^(14a), C₂₋₆ alkenyl substituted with0-2 R^(14a), C₂₋₆ alkynyl substituted with 0-2 R^(14a), —(CH₂)_(r)—C₃₋₁₀carbocycle substituted with 0-3 R^(g), or —(CH₂)_(r)-5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, NR^(f), O, and S(O)_(p), wherein said heterocycle is substituted with0-3 R^(g); R^(14a) is, independently at each occurrence, H, C₁₋₄ alkyl,OR^(f), Cl, F, Br, I, ═O, CF₃, CN, NO₂, NR¹²R¹³, —C(O)R^(f),—C(O)OR^(f), —C(O)NR¹²R¹³, or —S(O)_(p)R^(f); R^(a) is, independently ateach occurrence, H, F, OCF₃, CF₃, —(CR^(f)R^(f))_(r)OR^(c),—(CR^(f)R^(f))_(r)SR^(c), CN, —(CR^(f)R^(f))_(r)NR¹²R¹³,—(CR^(f)R^(f))_(r)C(O)R^(c), —(CR^(f)R^(f))_(r)C(O)OR^(c),—(CR^(f)R^(f))_(r)C(O)NR¹²R¹³, —(CR^(f)R^(f))_(r)NR¹⁴C(O)R^(d),—(CR^(f)R^(f))_(r)S(O)_(p)NR¹²R¹³, —(CR^(f)R^(f))_(r)S(O)R^(d),—(CR^(f)R^(f))_(r)S(O)₂R^(d), C₁₋₄ alkyl substituted with 1-5 fluorine,—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(e), or —(CH₂)_(r)-5-to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, NR^(f), O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R_(e); R^(b) is, independently at each occurrence,H, ═O, F, Cl, Br, I, —(CH₂)_(r)—OR^(c), SR^(c), CN, NO₂, CF₃, OCF₃,—(CR^(f)R^(f))_(r)NR¹²R¹³, —C(O)R^(c), —(CH₂)_(r)—C(O)OR^(c),—(CH₂)_(r)—C(O)NR¹²R¹³, —NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³, —S(O)R^(d),—S(O)₂R^(d), C₁₋₄ haloalkyl, C₁₋₄ haloalkyloxy-, C₁₋₆ alkyl substitutedwith 0-2 R^(a), C₂₋₆ alkenyl substituted with 0-2 R^(a), C₂₋₆ alkynylsubstituted with 0-2 R^(a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with0-3 R_(e), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, NR^(f), O, andS(O)_(p), wherein said heterocycle is substituted with 0-3 R^(e); R^(c)is, independently at each occurrence, H, —OP(O)(OEt)₂, C₁₋₈ alkylsubstituted with 0-2 R^(e), C₂₋₈ alkenyl substituted with 0-2 R_(e),C₂₋₈ alkynyl substituted with 0-2 R_(e), —(CR^(f)R^(f))_(r)—C₃₋₈cycloalkyl substituted with 0-2 R_(e), —(CR^(f)R^(f))_(r)—C₆₋₁₀ arylsubstituted with 0-2 R^(e), or —(CR^(f)R^(f))_(r)-5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, NR^(f), O, and S(O)_(p), wherein said heterocycle is substituted with0-2 R^(e); R^(d) is, independently at each occurrence, CF₃, OH, C₁₋₄alkoxy, C₁₋₆ alkyl, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-2R^(e), or —(CH₂)_(r)-5- to 10- membered heterocycle comprising: carbonatoms and 1-4 heteroatoms selected from N, NR^(f), O, and S(O)_(p),wherein said heterocycle is substituted with 0-2 R^(e); R^(e) is,independently at each occurrence, H, ═O, —(CH₂)_(r)—OR^(f), F, Cl, Br,I, CN, NO₂, —(CH₂)_(r)—NR¹²R¹³, —C(O)R^(f), —(CH₂)_(r)—C(O)OR^(f),—NR¹⁴C(O)R^(f), —(CH₂)_(r)—C(O)NR¹²R¹³, —SO₂NR¹²R¹³, —NR¹⁴SO₂NR¹²R¹³,—NR¹⁴SO₂-C₁₋₄ alkyl, —NR¹⁴SO₂CF₃, —NR¹⁴SO₂-phenyl, —S(O)₂CF₃,—S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, —(CF₂)_(r)CF₃, Si(C₁₋₄ alkyl)₃,C₁₋₈ alkyl substituted with 0-2 R^(g), C₂₋₈ alkenyl substituted with 0-2R^(g), C₂₋₈ aLkynyl substituted with 0-2 R^(g), —(CH₂)_(r)—C₃₋₈cycloalkyl substituted with 0-2 R^(g), —(CH₂)_(r)—C₆₋₁₀ aryl substitutedwith 0-2 R^(g), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, NR^(f), O, andS(O)_(p), wherein said heterocycle is substituted with 0-2 R^(g);alternatively, two R^(e) groups, together with the atoms to which theyare attached, form a 5- to 7-membered carbocyclic or heterocyclic ringcomprising: carbon atoms and 0-2 heteroatoms selected from N, NR^(f), O,and S(O)_(p), 0-1 carbonyl and 0-3 double bonds, wherein saidcarbocyclic or heterocyclic ring is substituted with 0-3 R^(g); R^(f)is, independently at each occurrence, H, F, C₁₋₆ alkyl, or—(CH₂)_(n)-phenyl; R^(g) is, independently at each occurrence, H, ═O,OR^(f), F, Cl, Br, I, CN, NO₂, —NR^(f)R^(f), —C(O)R^(f), —C(O)OR^(f),—NR^(f)C(O)R^(f), —C(O)NR^(f)R^(f), —SO₂NR^(f)R^(f),—NR^(f)SO₂NR^(f)R^(f), —NR^(f)SO₂-—₁₋₄ alkyl, —NR^(f)SO₂CF₃,—NR^(f)SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl,—(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl; R^(h) is,independently at each occurrence, C₁₋₆ alkyl substituted with 0-2 R^(g),or —(CH₂)_(n)-phenyl substituted with 0-2 R^(g), or —(CH₂)_(n)-5- to10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, NR^(f), O, and S(O)_(p), wherein said heterocycle issubstituted with 0-2 R^(g); R^(i) is, independently at each occurrence,H, C₁₋₆ alkyl substituted with 0-2 R^(g), —(CH₂)_(n)-phenyl substitutedwith 0-2 R^(g), or —(CH₂)_(n)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, NR^(f), O, andS(O)_(p), wherein said heterocycle is substituted with 0-2 R^(g); n, ateach occurrence, is selected from 0, 1, 2, 3, and 4; p, at eachoccurrence, is selected from 0, 1, and 2; and r, at each occurrence, isselected from 0, 1, 2, 3, and 4; provided that: i) when R⁵ is pyridylsubstituted with NO₂, then ring A is other than pyridyl substituted withNO₂; ii) when Y is S, ring B is phenylene or phenylene substituted withCl, R⁵ is phenyl substituted with Cl, then ring A is other than pyridylsubstituted with CO₂H; iii) when Y is S, ring B is phenylene, R⁵ isphenyl substituted with —NH— pyridyl, then ring A is other than pyridyl;iv) when Y is O, ring B is phenylene substituted with Cl, R⁵ is pyridyl,then ring A is other than trizolyl substituted with CO₂H; or v) when Yis O, ring B is phenylene, R⁵ is phenyl substituted with —NH-thiazolylor —NH-(4-Me-thiazolyl), then ring A is other than thiazolyl or4-Me-thiazolyl.
 2. A compound according to claim 1, wherein: ring B ispyridyl substituted with 0-3 R⁷.
 3. A compound according to claim 1,wherein: ring A is substituted with 0-3 R¹ and selected from:


4. A compound according to claim 1, wherein: ring B is

R⁷ and R^(7a) are H, Me, Cl, Br, CN, OMe, SMe, NHMe, NH₂, NMe₂, or—NH(4-OMe-Ph); R⁸ and R^(8b) are H, Me, Cl, Br, CN, NMe₂, or—N(Me)(4-OMe-Ph); —X is NH; and Y is O, S, or NH.
 5. A compound ofFormula (II):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orsolvates thereof, wherein: ring A is selected from:

alternatively, ring A is substituted with 0-3 R¹ and is selected from:

R¹, R^(1a), R^(1b), R^(1c), R^(1d), and R^(1e) are, independently ateach occurrence, C₁₋₆ alkyl substituted with 0-2 R^(a), C₂₋₆ alkenylsubstituted with 0-2 R^(a), C₂₋₆ alkynyl substituted with 0-2 R^(a), Br,CN, CF₃, —CF₂CF₃, —C(NH₂)═N(OH), C(O)R^(c), —CH(═NOH), —C(O)OR^(c),NR¹²R¹³, —C(O)NR¹²R¹³, —CON(Me)(CH₂)₂OH, —CO-morpholin-4-yl,—SO₂-morpholin-4-yl, —S(O)_(p)NR¹²R¹³, —(CH₂)_(r)—C₃₋₆ cycloalkylsubstituted with 0-2 R^(b), —(CH₂)_(r)-adamantyl substituted with 0-2R^(b), —(CH₂)_(r)-phenyl substituted with 0-4 R^(b), —(CH₂)_(r)-naphthylsubstituted with 0-4 R^(b), —(CH₂)_(r)-3- to 10-membered heterocyclesubstituted with 0-4 R^(b), wherein said heterocycle is selected from:aziridinyl, azetidinyl, pyrrolidinyl, furanyl, imidazolyl, oxadiazolyl,thienyl, pyrrolyl, isoxazolyl, triazolyl, tetrazolyl, pyridinyl,pyrazinyl, pyrirnidinyl, piperdinyl, morpholinyl, piperazinyl,1,3-benzodioxolyl, benzothienyl, isoindolinyl, 1,4-diazacycloheptanyl,tetrahydroisoquinolyl, and

alternatively, R^(1a) and R^(1b) or R^(1d) and R^(1e) are combined withthe carbon atoms to which they attached, form a 5- to 6-memberedcarbocycle or heterocycle comprising: carbon atoms and 0-3 additionalheteroatoms selected from N, NR¹¹, O, and S(O)_(p), 0-2 carbonyl, and0-1 additional double bond, wherein said carbocycle and heterocycle aresubstituted with 0-3 R^(b); alternatively, two R¹s are combined with thecarbon atoms to which they attached, form a 5- to 6-membered carbocycleor heterocycle comprising: carbon atoms and 0-3 additional heteroatomsselected from N, NR¹¹, O, and S(O)_(p), 0-2 carbonyl, and 0-1 additionaldouble bond, wherein said carbocycle and heterocycle are substitutedwith 0-3 R^(b); R⁵ is phenyl substituted with 1-4 R^(5a); R^(5a) is,independently at each occurrence, F, Cl, Br,1,-(CR^(i)R^(i))_(r)—OR^(c), SR^(c), CN, CF₃, —CF₂CF₃, OCF₃, —OCF₂CF₂H,—OCF₂CF₃, —NR¹²R¹³, —C(O)R^(c), —C(O)OR^(c), —C(O)NR¹²R¹³,—NR¹⁴C(O)R^(d), —S(O)_(p)NR¹²R¹³, —S(O)R^(d), —S(O)₂R^(d), —Si(Me)₃,Si(C₁₋₄ alkyl)₃, C₁₋₄ haloalkyl, C₁₋₄ haloalkyloxy-, C₁₋₄ alkyloxy-,C₁₋₄ alkylthio-, C₁₋₄ alkyl-C(O)—, C₁₋₄ alkyl-O—C(O)—, C₁₋₄alkyl-C(O)NH—, C₁₋₈ alkyl substituted with 0-2 R^(a), C₂₋₈ alkenylsubstituted with 0-2 R^(a), C₂₋₈ alkynyl substituted with 0-2 R^(a),—(CR^(f)R^(f))_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(e), or—(CR^(f)R^(f))_(r)-5- to 10-membered heterocycle comprising: carbonatoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(e); alternatively,two R^(5a) groups attached to two adjacent carbon atoms, together withthe carbon atoms to which they are attached, form a 5- to 7-memberedcarbocyclic or heterocyclic ring comprising: carbon atoms and 0-2heteroatoms selected from N, NR¹¹, O, and S(O)_(p), 0-1 carbonyl and 0-3double bonds, wherein said carbocyclic or heterocyclic ring issubstituted with 0-3 R^(e); R⁷ is H, Br, CN, NH₂, NMe₂, or—NH(4-OMe-Ph); R⁸ is H, Br, CN, NMe₂, or —N(Me)(4-OMe-Ph); R¹¹ is,independently at each occurrence, H, —COPh, —COBn, —SO₂Me, —SO₂Ph,—SO₂Bn, C₁₋₆ alkyl substituted with 1-5 fluorine,—(CR^(f)R^(f))_(r)C(O)NR¹²R¹³, C₁₋₄ alkyl substituted with 0-2 R^(a),—(CH₂)_(r)C₃₋₆ cycloalkyl substituted with 0-2 R^(b), —(CH₂)_(r)-phenylsubstituted with 0-3 R^(b), —CHMe-phenyl substituted with 0-3 R^(b), or—(CH₂)_(r)-5- to 10-membered heterocycle substituted with 0-3 R^(b);wherein said heterocycle is selected from: furanyl, thienyl, thiazolyl,pyridyl, and indolyl; R¹² is, independently at each occurrence, H, C₁₋₆alkyl substituted with 1-5 fluorine, —(CR^(f)R^(f))_(r)C(O)NR^(f)R^(f),C₁₋₆ alkyl, —(CH₂)_(r)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, —(CH₂)_(r)-5-to 6-membered heterocycle selected from pyrrolidinyl, furanyl, thienyl,pyrrolyl, isoxazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl,pyrimidinyl, piperdinyl, morpholinyl, and piperazinyl; wherein saidalkyl and phenyl are substituted with 0-2 R^(g); said 5- to 10-memberedheterocycle is substituted with with 0-2 R^(g); R¹³ is, independently ateach occurrence, H, C₁₋₆ alkyl, or —(CH₂)_(n)-phenyl; alternatively, R¹²and R¹³, when attached to the same nitrogen, combine to form a 5- to10-membered heterocyclic ring comprising: carbon atoms and 1-2additional heteroatoms selected from N, NR^(f), O, and S(O)_(p); R¹⁴ is,independently at each occurrence, H, C₁₋₆ alkyl, C₂₋₆ alkenyl,—(CH₂)_(r)-phenyl carbocycle substituted with 0-3 R^(g), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, NR^(f), O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(g); R^(a) is, independently ateach occurrence, H, F, OCF₃, CF₃, —(CR^(f)R^(f))_(r)OR^(c),—(CR^(f)R^(f))_(r)SR^(c), CN, —(CR^(f)R^(f))_(r)NR¹²R¹³,—(CR^(f)R^(f))_(r)C(O)R^(c), —(CR^(f)R^(f))_(r)C(O)OR^(c),—(CR^(f)R^(f))_(r)C(O)NR¹²R¹³, —(CR^(f)R^(f))_(r)NR¹⁴C(O)R^(d),—(CR^(f)R^(f))_(r)S(O)_(p)NR¹²R¹³, —(CR^(f)R^(f))_(r)S(O)R^(d),—(CR^(f)R^(f))_(r)S(O)₂R^(d), C₁₋₄ alkyl substituted with 1-5 fluorine,—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(e), or —(CH₂)_(r)-5-to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, NR^(f), O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R^(e); R^(b) is, independently at each occurrence,C₁₋₆ alkyl substituted with 0-2 R^(a), C₂₋₆ alkenyl substituted with 0-2R^(a), C₂₋₆ alkynyl substituted with 0-2 R^(a), F, Cl, Br, CF₃, —OCF₃,—(CH₂)_(r)—OR^(c), —(CH₂)_(r)—C(O)OR^(c), —(CR^(f)R^(f))_(r)NR¹²R¹³,—(CH₂)_(r)—C(O)NR¹²R¹³, CN, —OCH₂C(Me)₂CH₂NMe₂, NO₂, —SO₂Me, OBn,—(CH₂)_(r)—C₃₋₆ cycloalkyl, —(CH₂)_(r)-phenyl substituted with 0-2R^(e), —(CH₂)_(r)-naphthyl substituted with 0-3 R^(e), —(CH₂)_(r)-5- to10-membered heterocycle substituted with 0-4 0-4 R^(e); wherein saidheterocycle is selected from: thienyl, thiazolyl, imidazolyl,tetrazolyl, pyrrolidinyl, morpholinyl, piperidinyl, azepanyl,morpholinyl, piperazinyl, pyridinyl, tetrahydropyranyl, ortetrahydroisoquinolinyl; R^(d) is, independently at each occurrence,CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl, —(CH₂)_(r)—C₃₋₁₀ carbocyclesubstituted with 0-2 R^(e), or —(CH₂)_(r)-5- to 10- membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, NR^(f), O,and S(O)_(p), wherein said heterocycle is substituted with 0-2 R^(e);R^(e) is, independently at each occurrence, H, ═O, —(CH₂)_(r)—OR^(f), F,Cl, Br, I, CN, NO₂, —(CH₂)_(r)—NR¹²R¹³, —C(O)R^(f),—(CH₂)_(r)—C(O)OR^(f), —NR¹⁴C(O)R^(f), —(CH₂)_(r)—C(O)NR¹²R¹³,—SO₂NR¹²R¹³, —NR¹ ⁴SO₂NR¹²R¹³, —NR¹⁴SO₂—C₁₋₄ alkyl, —NR¹⁴SO₂CF₃,—NR¹⁴SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)-C₁₋₄ alkyl, —S(O)_(p)-phenyl,—(CF₂)_(r)CF₃, Si(C₁₋₄ alkyl)₃, C₁₋₈ alkyl substituted with 0-2 R^(g),C₂₋₈ alkenyl substituted with 0-2 R^(g), C₂₋₈ alkynyl substituted with0-2 R^(g), —(CH₂)_(r)—C₃₋₈ cycloalkyl substituted with 0-2 R^(g),—(CH₂)_(r)—C₆₋₁₀ aryl substituted with 0-2 R^(g), or —(CH₂)_(r)-5- to10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, NR^(f), O, and S(O)_(p), wherein said heterocycle issubstituted with 0-2 R_(g); alternatively, two R^(e) groups, togetherwith the atoms to which they are attached, form a 5- to 7-memberedcarbocyclic or heterocyclic ring comprising: carbon atoms and 0-2heteroatoms selected from N, NR^(f), O, and S(O)_(p), 0-1 carbonyl and0-3 double bonds, wherein said carbocyclic or heterocyclic ring issubstituted with 0-2 R_(g); R^(f) is, independently at each occurrence,H, F, C₁₋₆ alkyl, or —(CH₂)_(n)-phenyl; R^(g) is, independently at eachoccurrence, H, ═O, OR^(f), F, Cl, Br, I, CN, NO₂, —NR^(f)R^(f),—C(O)R^(f), —C(O)OR^(f), —NR^(f)C(O)R^(f), —C(O)NR^(f)R^(f),—SO₂NR^(f)R^(f), —NR^(f)SO₂NR^(f)R^(f), —NR^(f)SO₂-C₁₋₄ alkyl,—NR^(f)SO₂CF₃, —NR^(f)SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)-C₁₋₄ alkyl,—S(O)_(p)-phenyl, —(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆alkynyl; R^(i) is, independently at each occurrence, H or C₁₋₆ alkyl; n,at each occurrence, is selected from 0, 1, 2, 3, and 4; p, at eachoccurrence, is selected from 0, 1, and 2; and r, at each occurrence, isselected from 0, 1, 2, 3, and
 4. 6. A compound according to claim 5,wherein: ring A is

R^(1a) and R^(1b), independently at each occurrence, H, C₁₋₆ alkylsubstituted with 0-2 R^(a), C₂₋₆ alkenyl substituted with 0-2 R^(a),C₂₋₆ alkynyl substituted with 0-2 R^(a), Br, CN, CF₃, —CF₂CF₃,—C(NH₂)═N(OH), C(O)R^(c), —C(O)OR^(c), NR¹²R¹³, —C(O)NR¹²R¹³,—CON(Me)(CH₂)₂OH, —SO₂-morpholin-4-yl, —S(O)_(p)NR¹²R¹³,—CO-(4-morpholinyl), —(CH₂)_(r)-phenyl substituted with 0-3 R^(b);—(CH₂)_(r)-3- to 10- membered heterocycle substituted with 0-3 R^(b);wherein said heterocycle is selected from: aziridinyl, pyrrolidinyl,furanyl, imidazolyl, oxadiazolyl, triazolyl, tetrazolyl, piperidinyl,morpholinyl, piperazinyl, pyridyl, pyrimidinyl, 1,3-benzodioxolyl,isoindolinyl, 1,4-diazacycloheptanyl, tetrahydroisoquinolinyl, or

alternatively, ring A is

R¹¹ is H, C₁₋₆ alkyl substituted with 1-5 fluorine, —CH₂CH₂O(C₁₋₄alkyl), —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³, C₁₋₆ alkyl, cyclopropylmethyl,cyclopentylmethyl, —(CH₂)₂OH, Bn, —COPh, —COBn, —SO₂Me, —SO₂Ph, —SO₂Bn,—(CH₂)_(r)-phenyl substituted with 0-2 R^(b), or —(CH₂)_(r)-5- to6-membered heterocycle substituted with 0-2 R^(b), wherein saidheterocycle is selected from: furanyl, thienyl, thiazolyl, and pyridyl;R^(a) is, independently at each occurrence, OH, OMe, —C(O)OR^(c),—(CR^(f)R^(f))_(r)NR¹²R¹³, —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³, C₁₋₄ alkylsubstituted with 1-5 fluorine, or —CO(4-morpholinyl); R^(b) is,independently at each occurrence, C₁₋₆ alkyl, F, CF₃, —OCF₃, OH, —CH₂OH,—CH₂CH₂OH, —CH₂CH₂CH₂OH, OMe, —CH₂OMe, —OCH₂C(Me)₂CH₂NMe₂, CO₂H,—CH₂CH₂CO₂H, CO₂Me, —CH₂CH₂CO₂Me, CO₂Et, CN, —CH₂NHMe, —CH₂NHEt,—CH₂NHBn, NMe₂, —CH₂NMe₂, —CH₂N(Me)Et, —CH₂N(Me)Bn, —CH₂CH₂CH₂N(Me)Et,NO₂, —SO₂Me, OBn, cyclopropylmethyl, tetrahydropyranyl, pyrrolidinyl,pyrrolidinylmethyl, or morpholinylethyl.
 7. A compound according toclaim 5, wherein: ring A is selected from:

R^(1c) is, independently at each occurrence, C₁₋₆ alkyl substituted with0-2 R^(a), C₂₋₆ alkenyl substituted with 0-2 R^(a), C₂₋₆ alkynylsubstituted with 0-2 R^(a), Br, CF₃, C(O)R^(c), —C(O)OR^(c), NR¹²R¹³,—C(O)NR¹²R¹³, —(CH₂)_(r)—C₃₋₆ cycloalkyl substituted with 0-2 R^(b),—(CH₂)_(r)-adamantyl substituted with 0-2 R^(b), —(CH₂)_(r)-phenylsubstituted with 0-3 R^(b), —(CH₂)_(r)-naphthyl substituted with 0-3R^(b), —C(Me)₂(CH₂)_(r)-piperazinyl substituted with 0-3 R^(b),—C(Me)₂(CH₂)_(r)CO-piperazinyl substituted with 0-3 R^(b), —(CH₂)_(r)-5-to 10-membered heterocycle substituted with 0-3 R^(b); wherein saidheterocycle is selected from: azetidinyl, pyrrolidinyl, furanyl,thienyl, pyrrolyl, isoxazolyl, triazolyl, pyridinyl, pyrazinyl,piperdinyl, piperazinyl, benzothienyl, isoindolinyl, andtetrahydroisoquinolinyl; R^(a) is, independently at each occurrence,—O(CH₂)₂OMe, —C(O)OR^(c), —(CR^(f)R^(f))_(r)NR¹²R¹³,—(CR^(f)R^(f))_(r)C(O)NR¹²R¹³, C₁₋₄ alkyl substituted with 1-5 fluorine,SPh, phenoxy substituted with 0-2 R^(e), or benzoxy substituted with 0-2R^(e); R^(b) is, independently at each occurrence, C₁₋₆ alkyl, C₁₋₄alkoxyl, F, Cl, CF₃, —OCF₃, OH, —CH₂OH, CN, —(CR^(f)R^(f))_(r)NR¹²R¹³,—CH₂NMe₂, NO₂, —SO₂Me, —(CH₂)_(r)—C₃₋₆ cycloalkyl, CH(Ph)₂,—(CH₂)_(r)-phenyl substituted with 0-2 R^(e), —(CH₂)_(r)-naphthylsubstituted with 0-3 R^(e), —(CH₂)_(r)-furyl substituted with 0-2 R^(e),—(CH₂)_(r)-thienyl substituted with 0-2 R^(e), —(CH₂)_(r)-thiazolylsubstituted with 0-2 R^(e), —(CH₂)_(r)-imidazolyl substituted with 0-2R^(e), piperazinyl substituted with 0-2 R^(e), or —(CH₂)_(r)-pyridinylsubstituted with 0-2 R^(e); and R^(e) is, independently at eachoccurrence, C₁₋₆ alkyl, F, Cl, CN, or Bn.
 8. A compound according toclaim 5, wherein: ring A is selected from:

R^(1d) and R^(1f) are, independently at each occurrence, C₁₋₆ alkylsubstituted with 0-2 R^(a), —C(O)OR^(c), —C(O)NR¹²R¹³, —(CH₂)_(r)-phenylsubstituted with 0-3 R^(b), —(CH₂)_(r)-naphthyl substituted with 0-3R^(b), —(CH₂)_(r)-5- to 1 0-membered heterocycle substituted with 0-3R^(b), wherein said heterocycle is selected from: thienyl, isoxazolyl,benzothienyl, and 1,3-benzodioxolyl; R^(a) is, independently at eachoccurrence, OMe or N(Me)Bn; and R^(b) is, independently at eachoccurrence, Me, F, Cl, Br, CH₂OH, CF₃, —CH₂NMe₂, —CH₂N(Me)Bn, CN, NO₂,—SO₂Me, 2-CH₂NH₂—Ph, —(CH₂)_(r)—C₃₋₆ cycloalkyl, —(CH₂)_(r)-phenyl,—(CH₂)_(r)-pyrrolidinyl, —(CH₂)_(r)-tetrazolyl, —(CH₂)_(r)-piperidinyl,—(CH₂)_(r)-azepanyl, —(CH₂)_(r)-morpholinyl, —(CH₂)_(r)-piperazinyl,—(CH₂)_(r)—(4-Bn-piperazinyl), or —(CH₂)_(r)-tetrahydroisoquinolinyl. 9.A compound according to claim 5, wherein: ring A is selected from:

R^(1d) and R^(1e) are, independently at each occurrence, CN,—C(O)OR^(c), NR¹²R¹³, or —C(O)NR¹²R¹³, C₁₋₆ alkyl substituted with 0-2R^(a), or —(CH₂)_(r)-phenyl substituted with 0-3 R^(b); R¹¹ is,independently at each occurrence, H, C₁₋₆ alkyl substituted with 1-5fluorine, —(CR^(f)R^(f))_(r)C(O)NR¹²R¹³, C₁₋₆ alkyl substituted with 0-2R^(a), C₂₋₆ alkenyl substituted with 0-2 R^(a), —(CH₂)_(r)—C₃₋₆cycloalkyl substituted with 0-2 R^(b), —(CH₂)_(r)-phenyl substitutedwith 0-3 R^(b), —CHMe-phenyl substituted with 0-3 R^(b), or—(CH₂)_(r)-5- to 10- membered heterocycle substituted with 0-3 R^(b);wherein said heterocycle is selected from: furanyl, thienyl, thiazolyl,pyridinyl, and indolyl; R^(a) is, independently at each occurrence,OR^(c), SR^(c), —C(O)OR^(c), —(CR^(f)R^(f))_(r)NR¹²R³,—(CR^(f)R^(f))_(r)C(O)NR¹²R¹³, or C₁₋₄ alkyl substituted with 1-5fluorine; and R^(b) is, independently at each occurrence, C₁₋₄ alkyl,C₁₋₄ alkoxyl, F, Cl, Br, CF₃, —OCF₃, CN, —(CR^(f)R^(f))_(r)NR¹²R¹³,—CH₂NMe₂, NO₂, or —SO₂Me.
 10. A compound according to claim 5, whereinthe compound is of Formula (IIa):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orsolvate thereof, wherein: R^(1a) is H, Me, Et, i-Pr, neopentyl, vinyl,1-Me-vinyl, cyclopentyl, 1-cyclopentenyl, cyclohexyl, 1-cyclohexenyl,Br, CF₃, —C(NH₂)═N(OH), —CH₂OH, -(CH₂)₂OH, —CH₂OMe, COMe, CO₂H, CO₂Me,CO₂Et, —CH₂CO₂H, —CH₂CO₂Et, CN, —N(Me)Et, —N(CH₂CH₂OMe)₂,—N(Me)CH₂CH₂NMe₂, —N(Me)CH₂CH₂CH₂NMe₂, —CH₂NHEt, —CH₂NH(i-Bu),—CH₂NH-neopentyl, —CH₂NHBn, —CH₂N(Me)Et, —CH₂N(Me)Pr, —CH₂N(Me)(i-Bu),—CH₂N(Me)(t-Bu), —CH₂N(Me)cyclohexyl, —CH₂N(Me)Ph, —CH₂N(Me)Bn,—CH₂N(i-Pr)Bn, —CH₂N(t-Bu)Bn, —CH₂N(Me)CH(Me)Ph, —CH₂N(Me)(CH₂)₂Ph,—CH₂N(Me)(CH₂)₃Ph, —CH₂N(Me)(CH₂-pyridin-3-yl), —CONH₂, —CONHMe,—CONHEt, —CONHPr, —CONH-neopentyl, —CONHPh, —CONHBn,—CONH(CH₂-pyridin-2-yl), —CONH(CH₂-pyridin-3-yl),—CONH(CH₂CH₂-pyridin-3-yl), —CH₂CONHBn, —CON(Me)₂, —CON(Me)Et,—CON(Me)Pr, —CON(Me)(t-Bu), —CON(Me)Bn, —CON(Me)(CH₂)₂OH,—CON(Me)(CH₂)₂Ph, —CON(Me)(CH₂)₃Ph, —CON(Me)(CH₂-pyridin-3-yl),—CH₂CON(Me)Et, —SO₂-morpholin-4-yl, —SO₂NHEt, —SO₂NHBn, —SO₂N(Me)Et,—SO₂N(Me)Bn, —SO₂N(Bn)₂, Ph, 2-Me-Ph, 3-Me-Ph, 4-Me-Ph, 4-(i-Pr)-Ph,4-(t-Bu)-Ph, 2-F-Ph, 3-CF₃-Ph, 4-CF₃-Ph, 2-OH-Ph, 3-OH-Ph, 4-OH-Ph,4-CH₂OH-Ph, 3-(-CH₂CH₂CH₂OH)-Ph, 4-(-CH₂CH₂CH₂OH)-Ph, 3-OMe-Ph,4-OMe-Ph, 3-OCF₃-Ph, 4-OCF₃-Ph, 2-CH₂OMe-Ph, 3-NMe₂-Ph, 4-NMe₂-Ph,2-(-CH₂NHMe)-Ph, 3-(-CH₂NHMe)-Ph, 4-(-CH₂NHMe)-Ph, 2-(-CH₂NHBn)-Ph,3-(-CH₂NHBn)-Ph, 4-(-CH₂NHBn)-Ph, 2-(-CH₂NMe₂)-Ph, 3-(-CH₂NMe₂)-Ph,4-(-CH₂NMe₂)-Ph, 2-(-CH₂N(Me)Bn)-Ph, 3-(-CH₂N(Me)Bn)-Ph,4-(-CH₂N(Me)Bn)-Ph, 3-(-CH₂CH₂CH₂N(Me)Et)-Ph, 4-(-CH₂CH₂CH₂N(Me)Et)-Ph,3-CO₂H-Ph, 4-CO₂H-Ph, 3-CO₂Me-Ph, 4-CO₂Me-Ph, 3-(-CH₂CH₂CO₂H)-Ph,4-(-CH₂CH₂CO₂H)-Ph, 3-(-CH₂CH₂CO₂Me)-Ph, 2-CN-Ph, 3-CN-Ph, 4-CN-Ph,4-SO₂Me-Ph, 2-OBn-Ph, 3-OBn-Ph, 4-OBn-Ph, 3-(-OCH₂C(Me)₂CH₂NMe₂)-Ph,4-(-OCH₂C(Me)₂CH₂NMe₂)-Ph, 2,4-diF-Ph, 3,5-diF-Ph, 2-F-4-Me-Ph,2-F-4-OMe-Ph, 3-F-4-OMe-Ph, 2-(-CH₂NMe₂)-4-OMe-Ph,3-(-CH₂NHMe)-4-OMe-Ph, 2-(-CH₂NHBn)-4-OMe-Ph, 2-(-CH₂N(Me)Bn)-4-OMe-Ph,3,4,5-triOMe-Ph, pyrrolidin-1-yl, 2-(CH₂OMe)-pyrrolidin-1-yl,3-(-N(Me)COMe)-pyrrolidin-1-yl, furan-3-yl, imidazol-1-yl, 3-Me-1,2,4-oxadiazol-5-yl, 5-Me-1 ,2,4-oxadiazol-3-yl,3-Ph-1,2,4-oxadiazol-5-yl, 1 H-tetrazol-5-yl, 1 H-1,2,4-triazol-3-yl,1-(i-Pr)-1 ,2,4-triazol-3-yl, piperidin-1-yl, 4-OH-piperidin-1-yl,3-OMe-piperidin-1-yl, 4-CH₂OH-piperidin-1-yl,2-(-CH₂CH₂OH)-piperidin-1-yl, 4-(-CH₂CH₂OH)-piperidin-1-yl,2-(-CH₂NMe₂)-piperidin-1-yl, 2-CO2Et-piperidin-1-yl,3-CO₂Et-piperidin-1-yl, 4-CO₂Et-piperidin-1-yl, 3-CON H₂-piperidin-1-yl,4-CONH₂-piperidin-1-yl, 3-CON(Et)₂-piperidin-1-yl,—N(Me)(1-Me-piperidin-4-yl), 4-(pyrrolidin-1-yl)-piperidin-1-yl,piperazin-1-yl, 4-Me-piperazin-1-yl, 4-Et-piperazin-1-yl,4-i-Pr-piperazin-1-yl, 4-(-CH₂CH₂OH)-piperazin-1-yl,4-(-CH₂CH₂OCH₂CH₂OH)-piperazin-1-yl, 4-COMe-piperazin-1-yl,4-CO₂Et-piperazin-1-yl, 4-Bn-piperazin-1-yl, pyridin-3-yl, pyridin-4-yl,—N(Me)(1-Me-pyrrolidin-3-yl), —N(Me)-CH₂-pyridin-3-yl,—N(Me)-CH₂-pyridin-4-yl, morpholin-4-yl, —CH₂-morpholin-4-yl,—CO-morpholin-4-yl, 2-OMe-pyrimidin-5-yl, 1,3-benzodioxol-4-yl,

R^(1b) is H, Me, Et, i-Pr, i-Bu, t-Bu, neopentyl, cyclopropyl,cyclobutyl, CH₂OH, —C(Me)₂CH₂OH, —C(Me)₂(CH₂)₂OH, —CH₂OMe, —CH₂OEt,CH₂O(i-Bu), —CH₂O(CH₂)₂OMe, CO₂Et, —CH₂CO₂(i-Pr), —(CH₂)₂CO₂Me,—(CH₂)₂CO₂Et, —C(Me)₂CH₂CO-morpholin-4-yl, —C(NMe)₂CO₂H, —C(Me)₂CO₂Me,—C(Me)₂CH₂CO₂H, —C(Me)₂CH₂CO₂Et, —C(Me)₂(CH₂)₂CO₂H, —C(Me)₂(CH₂)₃CO₂H,CN, —C(Me)₂CH₂CN, CF₃, —CH₂CF₃, —CF₂CF₃, —CH(i-Bu)NH₂, —CH₂NMe₂,—C(Me)₂CH₂N(Me)Et, —C(Me)₂(CH₂)₂N(Me)Et, —C(Me)₂(CH₂)₂N(Me)(i-Bu),—CH₂OCH₂CH₂NEt₂, —CONHMe, —CONHEt, —CONHPr, —CONH(t-Bu),—CONH-neopentyl, —CONHPh, —CONHBn, —CONMe₂, —CON(Me)(t-Bu), —CON(Me)Bn,—C(Me)₂CON(Me)Et, —C(Me)₂CH₂CONH₂, —C(Me)₂CH₂CONHEt, —C(Me)₂CH₂CONHBn,—C(Me)₂CH₂CON(Me)Et, —C(Me)₂CH₂CON(Me)(i-Bu), —C(Me)₂CH₂CON(Me)Bn,—CH(i-Bu)NHCO₂(t-Bu), Ph, 4-Me-Ph, 3-F-Ph, 2-CH₂OH-Ph, 3-CH₂OH-Ph,4-CH₂OH-Ph, 2-OMe-Ph, 3-OMe-Ph, 4-OMe-Ph, 2-(CH₂NHEt)-Ph,2-(CH₂NHBn)-Ph, 2-(CH₂NMe₂)-Ph, 2-(CH₂N(Me)Et)-Ph, 2-(CH₂N(Me)Bn)-Ph,3-(CH₂N(Me)Bn)-Ph, 4-(CH₂N(Me)Bn)-Ph, 2-CO₂Et-Ph, 4-CF₃-Ph, 4-OCF₃-Ph,4-CN-Ph, 2-NO₂-Ph, 3-NO₂-Ph, 4-NO₂-Ph, —C(Me)₂(CH₂)₂(pyrrolidin-1-yl),—CH₂OCH₂(1-Me-piperidin-3-yl), —CH₂OCH₂(1-Me- piperidin-4-yl),alternatively,

R⁵ is 2-i-Pr-Ph, 2-t-Bu-Ph, 2-OCF₃-Ph, 2-CO₂Me-Ph,

R⁷ is H, Br, CN, NH₂, NHMe, NMe₂, or —NH(4-OMe-Ph); R⁸ is H, Br, CN,NHMe, NMe₂, or —N(Me)(4-OMe-Ph); and R¹¹ is H, Pr, i-Pr, Bu, i-Bu,isopentyl, —CH₂CH(Me)Et, —CH₂CH(Et)₂, —CH₂CH₂CMe₃, cyclopropylmethyl,cyclopentylmethyl, —(CH₂)₂OH, Bn, —COMe, —COPh, —COBn, —SO₂Me, —SO₂Ph,—SO₂Bn, Bn, 2-Me-Bn, 3-Me-Bn, 3-OH-Bn, 4-OH-Bn, 2-OMe-Bn, 3-OMe-Bn,4-OMe-Bn, 2-F-Bn, 3-OCF₃-Bn, 3-CN-Bn, 4-CN-Bn, phenethyl,2-furanylmethyl, 3-furanylmethyl, 3-pyridylmethyl, or 4-pyridylmethyl.11. A compound according to claim 10, wherein: R⁶ is 2-t-Bu-Ph; R⁷ is H;and R⁸ is H.
 12. A compound according to claim 5, wherein the compoundis of Formula (IIb):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orsolvate thereof, wherein: R^(1c) is H, i-Pr, t-Bu, neopentyl,cyclopropyl, 1-Ph-cyclopropyl, cyclobutyl, cycopentyl, cyclohexyl,4-NHBn-cyclohexyl, 4-N(Me)Bn-cyclohexyl, —CH₂OBn, —CH₂O(CH₂)₂OMe, CO₂H,CO₂Et, —C(Me)₂(CH₂)₂CO₂Me, —CH₂N(Me)Bn, —(CH₂)₃N(Me)Bn,—C(Me)₂(CH₂)₃N(Me)Bn, —CON(Me)Bn, —C(Me)₂CH₂CON(Me)Bn,—C(Me)₂(CH₂)₂CON(Me)Bn, Ph, phenethyl, 3-Me-Ph, 4-Me-Ph, 4-t-Bu-Ph,3-OH-Ph, 2-OMe-Ph, 4-OMe-Ph, 4-F-Ph, 2-Cl-Ph, 3-Cl-Ph, 4-CF₃-Ph,3-OCF₃-Ph, 4-OCF₃-Ph, 4-CN-Ph, 3-NMe₂-Ph, 4-NMe₂-Ph, 2-CH₂NMe₂-Ph,3-CH₂NMe₂-Ph, 4-CH₂NMe₂-Ph, 4-NO₂-Ph, 4-Ph-Ph, 3,5-diCl-Ph,4-(imidazol-1-yl)-Ph, 3-(4-Bn-piperazin-1-yl)-Ph,4-(4-Bn-piperazin-1-yl)-Ph, 4-F-Bn, 4-OMe-Bn, 4-NMe₂-Bn, naphth-2-yl,1-Bn-pyrrolidin-3-yl, thien-2-yl, —CH₂-thien-2-yl, 1-Me-pyrrol-2-yl,2,5-diMe-furan-3-yl, isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 1-neohexyl-4-Me-piperidin-4-yl,1-(CH₂-cyclohexyl)-4-Me-piperidin-4-yl, 2-Ph-piperidin-4-yl,1-Me-2-Ph-piperidin-4-yl, 1-Bn-piperidin-3-yl, 1-Bn-piperidin-4-yl,1-Bn-4-Me-piperidin-4-yl, 1-(2-CI-Bn)-piperidin-4-yl,1-(2-Cl-Bn)-4-Me-piperidin-4-yl, 1-(2-CN-Bn)-4-Me-piperidin-4-yl,1-(3-CN-Bn)-4-Me-piperidin-4-yl, 1-(4-CN-Bn)-4-Me-piperidin-4-yl,1-(2,4-diF-Bn)-4-Me-piperidin-4-yl, 1-(2,5-diF-Bn)-4-Me-piperidin-4-yl,1-(2,6-diCl-Bn)-4-Me-piperidin-4-yl,1-(CH₂-naphth-1-yl)-4-Me-piperidin-4-yl,1-(CH₂-furan-3-yl)-4-Me-piperidin-4-yl,1-(CH₂-thien-2-yl)-4-Me-piperidin-4-yl,1-(CH₂-thiazol-2-yl)-4-Me-piperidyin-4-yl,1-(CH₂-pyrid-2-yl)-4-Me-piperid-4-yl,1-(CH₂-pyrid-3-yl)-4-Me-piperid-4-yl,1-(1-Bn-piperid-4-yl)-piperid-4-yl, —CH₂-(4-Bn-piperazin-1-yl),—(CH₂)₃-(4-Bn-piperazin-1-yl), —C(Me)₂(CH₂)₃-(4-Bn-piperazin-1-yl),—C(Me)2(CH₂)₂CO(4-Bn-piperazin-1-yl),

R⁵ is 2-t-Bu-Ph, 2-Br-Ph, 2-CO₂Me-Ph, 3-CO₂Et-Ph,


13. A compound according to claim 5, wherein the compound is of Formula(IIc):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orsolvate thereof, wherein: R^(1c) is Me, i-Pr, t-Bu, cyclopropyl, Br,CF₃, —CH₂OPh, —CH₂O(4-t-Bu-Ph), —CH₂O(2-Cl-Ph), —CH₂O(4-Cl-Ph), —CH₂SPh,—CH₂N(Me)Bn, Ph, 4-Me-Ph, 4-t-Bu-Ph, 3-OH-Ph, 4-OMe-Ph, 2-F-Ph, 3-F-Ph,4-Cl-Ph, 3-CF₃-Ph, 4-CF₃-Ph, 3-NO₂-Ph, 4-SO₂Me-Ph, 3-Cl-4-F-Ph,3,4-diOMe-Ph, 3,5-diOMe-Ph, 3,5-diCl-Ph, 2,6-diCl-Bn, pyridin-2-yl,pyridin-3-yl, pyridin-4-yl, 2,6-diCl-pyridin-4-yl, furan-3-yl,thien-2-yl, pyrazin-2-yl, —CH₂-1-(1 ,2,4-triazol-1-yl),1-Bn-piperidin-4-yl, —CH₂-piperidin-1-yl, —CH₂-4-Bn-piperazin-1-yl,benzo[b]thien-3-yl, or

and R⁵ is 2-t-Bu-Ph, 2-Br-Ph, 2-CO₂Me-Ph, 3-CO₂Et-Ph,


14. A compound according to claim 5, wherein the compound is of Formula(IId₁) or Formula (IId₂):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orsolvate thereof, wherein: R^(1d) is, independently at each occurrence,—CH(OMe)₂, —CH₂N(Me)Bn, CO₂Et, —CON(Me)Bn, Ph. 2-F-Ph, 3-F-Ph, 2-Cl-Ph,3-Cl-Ph, 3-CH₂OH-Ph, 3-CH₂NMe₂-Ph, 4-CF₃-Ph, 3-CN-Ph, 4-CN-Ph, 3-NO₂-Ph,4-NO₂-Ph, 4-SO₂Me-Ph, 4-cyclohexyl-Ph, 4-Ph-Ph, 3-CH₂N(Me)Bn-Ph,3-(CH₂-piperidin-1-yl)-Ph, 3-(CH₂-morpholin-4-yl)-Ph,3-(CH₂-piperazin-1-yl)-Ph, 3-(CH₂-(4-Me-piperazin-1-yl))-Ph,2,4-diMe-Ph, 3-Me-4-Cl-Ph, 3,4-diCl-Ph, 2-F-4-Br-Ph, 3-NO₂-4-Cl-Ph,2-F-4-(2-CH₂NMe₂-Ph)-Ph, 2-F-4-(pyrrolidin-1-yl)-Ph,4-(1H-tetrazol-5-yl)-Ph, 2-F-4-(piperidin-1-yl)-Ph,2-F-4-(1-azepanyl)-Ph, 2-F-4-(4-Bn-piperazin-1-yl)-Ph, 2-F-4-Cl-5-Me-Ph,naphth-2-yl, 3-Ph-isoxazol-5-yl, 3-Ph-5-Me-isoxazol-4-yl,5-Ph-thien-2-yl, pyridin-3-yl, pyridin-4-yl, benzo[b]thien-3-yl,1,3-benzodioxol-4-yl, or 3-(CH₂-1,2,3,4-tetrahydroisoquinolin-2-yl)-Ph.15. A compound according to claim 5, wherein the compound is of Formula(IIe₁) or Formula (IIe₂):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, orsolvate thereof, wherein: R^(1h) is, independently at each occurrence,CN, CO₂Et, CONMe₂, Ph, 2-F-Ph, or 4-CF₃-Ph; and R¹¹ is, independently ateach occurrence, H, Me, n-Bu, neohexyl, —CH₂CH═C(Me)₂, —(CH₂)₂OMe,—(CH₂)₂SMe, —(CH₂)₂SEt, —(CH₂)₂S(i-Pr), —(CH₂)₃SMe, —(CH₂)₃N(Me)₂,—(CH₂)₂O(CH₂)₂Cl, —(CH₂)₂O(4-Cl-Ph), —CH₂-cyclopropyl, Ph, Bn, 2-Cl-Bn,3-Cl-Bn, 2-Br-Bn, 4-Br-Bn, 4-CF₃-Bn, 4-SMe-Bn, 2-F-6-Cl-Bn, 2-Cl-4-F-Bn,2-F-4-Br-Bn, 3,5-diCl-Bn, —CHMe-Ph, phenethyl, 4-Cl-phenethyl,—CH₂-thien-2-yl, —(CH₂)₂-thien-2-yl, —(CH₂)₂-thien-3-yl,—(CH₂)₂-(4-Me-thiazol-5-yl), —CHMe-furan-2-yl, —(CH₂)₂-pyridin-2-yl,—(CH₂)₂-pyridin-4-yl, or —(CH₂)₂-indol-3-yl.
 16. A compound according toclaim 5, wherein: R⁵ is a phenyl substituted with 1-2 R^(5a); R^(5a) is,independently at each occurrence, F, Cl, Br, I, CN, —C(Me)₂CN, CF₃,—CF₂CF₃, OCF₃, —OCF₂CF₂H, —OCF₂CF₃, C₁₋₈ alkyl, C₂₋₈ alkenyl, OH, C₁₋₄alkyloxy, SMe, S(i-Pr), —C(Me)₂OMe, —C(Me)₂OEt, —C(Me)₂OPr,—CHMeO(CH₂)₂OMe, —C(Me)₂OBu, —C(Me)₂O(CH₂)₂OMe, —C(Me)(OMe)CH₂OMe,—C(Me)₂O(CH₂)₂N(i-Bu)₂, —C(Me)₂O(CH₂)₂S(i-Bu), —C(Me)₂O(CH₂)₂S(O)(i-Bu),—C(Me)₂O(CH₂)₂S(furan-2-ylnethyl), —C(Me)₂O(CH₂)₂S(Pyridin-2-yl),—C(Me)₂O(CH₂)₂S(O)₂(pyridin-2-yl), —C(Me)₂CH₂OSi(Me)₂(t-Bu),—C(Me)₂O(CH₂)₂Si(Me)₂(t-Bu), —C(Et)₂OH, —C(Pr)₂OH, —C(CH₂CH═CH₂)₂OH,—C(CH₂CH═CH₂)₂OMe, —C(Et)₂OMe, —C(Et)₂OEt, —C(Et)₂OPr, COMe, COPh,CO₂Me, CO₂Et, —NH(i-Bu), —CH═CHCO₂(t-Bu), —OCH₂CO₂(t-Bu), C₃₋₇cycloalkyl, C₃₋₇ cycloalkenyl, Ph, Bn, naphthyl, 1-pyrrolidinyl,5-isoxazolyl, N-morpholinyl, 1-piperidinyl, —SiMe₃,

alternatively, R⁵ is:


17. A compound according to claim 5, wherein: R⁵ is 2-i-Pr-Ph,2-t-Bu-Ph, 2-Br-Ph, 2-OCF₃-Ph, 2-CO₂Me-Ph, 3-CO₂Et-Ph,


18. A compound according to claim 1, wherein the compound is selectedfrom the exemplified examples or a stereoisomer, tautomer,pharmaceutically acceptable salt, or solvate thereof.
 19. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of claim 1.20. A method for treating a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a compound of claim
 1. 21. A method according to any one ofclaims 20, wherein the thromboembolic disorder is selected from thegroup consisting of arterial cardiovascular thromboembolic disorders,venous cardiovascular thromboembolic disorders, and thromboembolicdisorders in the chambers of the heart.
 22. A method according to claim20, wherein the thromboembolic disorder is selected from unstableangina, an acute coronary syndrome, atrial fibrillation, firstmyocardial infarction, recurrent myocardial infarction, ischemic suddendeath, transient ischemic attack, stroke, atherosclerosis, peripheralocclusive arterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis.